Diaryl macrocycles as modulators of protein kinases

ABSTRACT

The present invention relates to certain diaryl macrocyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 61/931,506 filed Jan. 24, 2014, Ser.No. 62/049,326 filed Sep. 11, 2014 and Ser. No. 62/106,301 filed on Jan.22, 2015, the entire contents of which are hereby incorporated byreference in their entirety.

TECHNICAL FIELD

The present invention relates to certain diaryl macrocyclic derivatives,pharmaceutical compositions containing them, and methods of using themto treat cancer, pain, neurological diseases, autoimmune diseases, andinflammation.

BACKGROUND

Protein kinases are key regulators for cell growth, proliferation andsurvival. Genetic and epigenetic alterations accumulate in cancer cellsleading to abnormal activation of signal transduction pathways whichdrive malignant processes. Manning, G. et al., Science 2002, 298,1912-1934. Pharmacological inhibition of these signaling pathwayspresents promising intervention opportunities for targeted cancertherapies. Sawyers, C., Nature 2004, 432, 294-297.

MET, along with RON, belongs to a unique subfamily of receptor tyrosinekinases, and is mainly produced in cells of epithelial or endothelialorigin. Park, M. et al., Cell 1986, 45, 895-904. Hepatocyte growthfactor (HGF), also known as scatter factor (SF), is the only knownnatural high-affinity ligand of MET, and is mainly expressed in cells ofmesenchymal origin. Bottaro, D. P. et al., Science 1991, 251, 802-804.HGF/MET signaling controls MET-dependent cell proliferation, survival,and migration processes that are critical for invasive growth duringembryonic development and postnatal organ regeneration, and are fullyactive in adults only for wound healing and tissue regenerationprocesses. Trusolino, L. et al., Nature Rev. Mol. Cell Biol. 2010, 11,834-848. The HGF/MET axis is frequently upregulated in many cancersthrough activating mutation, gene amplification, aberrant paracrine, orautocrine ligand production, and is strongly linked with tumorigenesis,invasive growth, and metastasis. Gherardi, E. et al., Nature Rev. Cancer2012, 12, 89-103. In addition, the activation of HGF/MET signaling isemerging as an important mechanism in resistance to EGFR and BRAFinhibitor treatments via MET amplification and/or upregulation ofstromal HGF. Engelman, J. A. et al., Science 2007, 316, 1039-1043;Wilson, T. R. et al., Nature 2012, 487, 505-509. Due to the role ofaberrant HGF/MET signaling in human oncogenesis, invasion/metastasis,and resistance, inhibition of the HGF/MET signaling pathway has greatpotential in cancer therapy.

ALK, along with leukocyte tyrosine kinase (LTK), is grouped within theinsulin receptor (IR) superfamily of receptor tyrosine kinases. ALK ismainly expressed in the central and peripheral nervous systemssuggesting a potential role in normal development and function of thenervous system. Pulford, K. et al., Cell Mol. Life Sci. 2004, 61, 2939.ALK was first discovered as a fusion protein, NPM (nucleophosmin)-ALK,encoded by a fusion gene arising from the t(2;5)(p23;q35) chromosomaltranslocation in anaplastic large cell lymphoma (ALCL) cell lines.Morris, S. W. et al., Science 1994, 263, 1281. More than twenty distinctALK translocation partners have been discovered in many cancers,including ALCL (60-90% incidence), inflammatory myofibroblastic tumors(IMT, 50-60%), non-small cell lung carcinomas (NSCLC, 3-7%), colorectalcancers (CRC, 0-2.4%), breast cancers (0-2.4%), and other carcinomas.Grande, E. et al., Mol. Cancer Ther. 2011, 10, 569-579. The ALK-fusionproteins are located in the cytoplasm, and the fusion partners with ALKplay a role in dimerization or oligomerization of the fusion proteinsthrough a coil-coil interaction to generate constitutive activation ofALK kinase function. Bischof, D. et al., Mol. Cell Biol., 1997, 17,2312-2325. EML4-ALK, which comprises portions of the echinodermmicrotubule associated protein-like 4 (EML4) gene and the ALK gene, wasfirst discovered in NSCLC, is highly oncogenic, and was shown to causelung adenocarcinoma in transgenic mice. Soda, M. et al., Nature 2007,448, 561-566. Oncogenic point mutations of ALK in both familial andsporadic cases of neuroblastoma. Mosse, Y. P. et al., Nature 2008, 455,930-935. ALK is an attractive molecular target for cancer therapeuticintervention because of the important roles in haematopoietic, solid,and mesenchymal tumors. Grande, supra.

The tropomyosin-related receptor tyrosine kinases (Trks) are thehigh-affinity receptor for neurotrophins (NTs), a nerve growth factor(NGF) family of proteins. Members of the Trk family are highly expressedin cells of neural origin. Activation of Trks (TrkA, TrkB, and TrkC) bytheir preferred neurotrophins (NGF to TrkA, brain-derived neurotrophicfactor [BDNF] and NT4/5 to TrkB, and NT3 to TrkC) mediates the survivaland differentiation of neurons during development. The NT/Trk signalingpathway functions as an endogenous system that protects neurons afterbiochemical insults, transient ischemia, or physical injury. Thiele, C.J. et al., Clin. Cancer Res. 2009, 15, 5962-5967. However, Trk wasoriginally cloned as an oncogene fused with the tropomyosin gene in theextracellular domain. The activating mutations caused by chromosomalrearrangements or mutations in NTRK1 (TrkA) has been identified inpapillary and medullary thyroid carcinoma, and recently in non-smallcell lung cancer. Pierotti, M. A. et al., Cancer Lett. 2006, 232, 90-98;Vaishnavi, A. et al., Nat. Med. 2013, 19, 1469-1472. Because Trks playimportant roles in pain sensation as well as tumor cell growth andsurvival signaling, inhibitors of Trk receptor kinases may providebenefits as treatments for pain and cancer.

Receptor tyrosine kinase AXL belongs to the TAM family of proteins andwas originally detected in patients with chronic myelogenous leukemia(CML) as an unidentified transforming gene. Verma, A. et al., Mol.Cancer Ther. 2011, 10, 1763-1773. The primary ligand for TAM receptorsis growth arrest-specific 6 protein (Gas6). AXL is ubiquitouslyexpressed and has been detected in a wide variety of organs and cells,including the hippocampus and cerebellum, monocytes, macrophages,platelets, endothelial cells (EC), heart, skeletal muscle, liver,kidney, and testis. Upregulation of Gas6/AXL has been reported in manyhuman cancers including colon, esophageal, thyroid, breast, lung, liver,and astrocytoma-glioblastoma. Id. Increased activation of AXL has beenobserved in EGFR-mutant lung cancer models in vitro and in vivo withacquired resistance to erlotinib in the absence of the EGFR T790Malteration or MET activation. Zhang, Z. et al., Nat. Genet. 2012, 44,852-860. Genetic or pharmacological inhibition of AXL restoredsensitivity to erlotinib in these tumor models. Increased expression ofAXL and, in some cases, of its ligand Gas6 was found in EGFR-mutant lungcancers obtained from individuals with acquired resistance to tyrosinekinase inhibitors. Id. Therefore, AXL is a promising therapeutic targetfor patients with EGFR-mutant lung cancer who acquired resistance toEGFR inhibitors.

Crizotinib (PF-02341066) is a tyrosine kinase drug targetingMET/ALK/ROS1/RON with moderate activity against TRKs and AXL. Cui, J. J.et al., J. Med. Chem. 2011, 54, 6342-6363. It was approved to treatcertain patients with late-stage (locally advanced or metastatic) NSCLCthat expresses the abnormal ALK fusion gene identified by a companiondiagnostic test (Vysis ALK Break Apart FISH Probe Kit). Similar toimatinib and other kinase inhibitor drugs, resistance invariablydevelops after a certain time of treatment with crizotinib. Theresistance mechanisms include ALK gene amplification, secondary ALKmutations, and aberrant activation of other kinases including KIT andEGFR. Katayama, R. et al., Sci. Transl. Med. 2012, 4, 120ra17. Based onthe clinical success of second generation ABL inhibitors for thetreatment of imatinib resistance in CML patients, a second generation ofALK inhibitors is emerging. These drugs target the treatment ofcrizotinib-refractory or resistant NSCLC patient with more potentinhibition against both wild and mutant ALK proteins. Gridelli, C. etal., Cancer Treat Rev. 2014, 40, 300-306.

By modulating multiple targets among the group of structurally relatedtyrosine kinases MET, ALK, AXL, and TRK, the compounds described hereinaddress crizotinib resistance, EGFR inhibitor drug resistance, and otherprimary indications with abnormal cell signaling due to MET, ALK, AXL,and/or TRK mutations and gene amplification. Compounds describe hereinare inhibitors of MET, wild and mutant ALKs, AXL, and TRKs and will beuseful in treating cancer patients with abnormal signaling from any oneor more of MET, ALK, AXL, or TRKs.

The Janus family of kinases (JAKs) include JAK1, JAK2, JAK3 and TYK2,and are cytoplastic tyrosine kinases required for the physiologicsignaling of cytokines and growth factors. Quintas-Cardama, A. et al.,Nat. Rev. Drug Discov. 2011, 10(2), 127-40; Pesu, M. et al., Immunol.Rev. 2008, 223, 132-142; Murray, P. J., J. Immunol. 2007, 178(5),2623-2329. JAKs activate by ligand-induced oligomerization, resulting inthe activation of downstream transcriptional signaling pathway calledSTAT (signal transducers and activators of transcription). Thephosphorylated STATs dimerize and translocate into nucleus to drive theexpression of specific genes involved in proliferation, apoptosis,differentiation, which are essential for hematopoiesis, inflammation andimmune response. Murray, supra.

Mouse knockout studies have implicated the primary roles of JAK-STATsignaling with some overlap between them. JAK1 plays a critical role inthe signaling of various proinflammatory cytokines such as IL-1, IL-4,IL-6, and tumor necrosis factor alpha (TNFα). Muller, M. et al., Nature1993, 366(6451), 129-135. JAK2 functions for hematopoietic growthfactors signaling such as Epo, IL-3, IL-5, GM-CSF, thrombopoietin growthhormone, and prolactin-mediated signaling. Neubauer, H. et al., Cell1998 93(3), 397-409. JAK3 plays a role in mediating immune responses,and TYK2 associates with JAK2 or JAK3 to transduce signaling ofcytokines, such as IL-12. Nosaka, T. et al., Science 1995, 270(5237),800-802; Vainchenker, W. et al., Semin. Cell. Dev. Biol. 2008, 19(4),385-393.

Aberrant regulation of JAK/STAT pathways has been implicated in multiplehuman pathological diseases, including cancer (JAK2) and rheumatoidarthritis (JAK1, JAK3). A gain-of-function mutation of JAK2 (JAK2V617F)has been discovered with high frequency in MPN patients. Levine, R. L.et al., Cancer Cell 2005, 7(4), 387-397; Kralovics, R. et al., N. Engl.J. Med. 2005, 253(17), 1779-1790; James, C. et al., Nature 2005,434(7037), 1144-1148; Baxter, E. J. et al. Lancet 2005, 365(9464),1054-1061. The mutation in the JH2 pseudokinase domain of JAK2 leads toconstitutively kinase activity. Cells containing JAK2V617F mutantationacquire cytokine-independent growth ability and often become tumor,providing strong rational for the development of JAK inhibitors astarget therapy.

Multiple JAK inhibitors in clinical trial showed significant benefit insplenomegaly and disease related constitutional symptoms for themyelofibrosis patients, including the first FDA-approved JAK2 inhibitorruxolitinib in 2011. Quintas-Cardama, supra; Sonbol, M. B. et al., Ther.Adv. Hematol. 2013, 4(1), 15-35; LaFave, L. M. et al., Trends Pharmacol.Sci. 2012, 33(11), 574-582. The recently collected clinical data relatedto ruxolitinib treatment indicated that JAK inhibitors work on both JAK2wild-type and JAK2 mutated cases. Verstovsek, S. et al., N. Engl. J.Med. 2012, 366(9), 799-807; Quintas-Cardama, A. et al., Blood 2010,115(15), 3109-3117. The discovery of selective inhibitors of JAK2 vsJAK1/3 remains an unsolved challenge. In addition, hyperactivation ofthe JAK2/signal transducers and activators of transcription 3(JAK2/STAT3) is responsible for abnormal dendritic cell differentiationleading to abnormal dendritic cell differentiation and accumulation ofimmunosuppressive myeloid cells in cancer (Nefedova, Y. et al., CancerRes 2005; 65(20): 9525-35). In Pten-null senescent tumors, activation ofthe Jak2/Stat3 pathway establishes an immunosuppressive tumormicroenvironment that contributes to tumor growth and chemoresistance(Toso, A. et al., Cell Reports 2014, 9, 75-89). Therefore, pharmacologicinhibition of the JAK2/STAT3 pathway can be an important new therapeuticstrategy to enhance antitumor activity via the regulation of antitumorimmunity.

ROS1 kinase is a receptor tyrosine kinase with an unknown ligand. Thenormal functions of human ROS1 kinase have not been fully understood.However, it has been reported that ROS1 kinase undergoes geneticrearrangements to create constitutively active fusion proteins in avariety of human cancers including glioblastoma, non-small cell lungcancer (NSCLC), cholangiocarcinoma, ovarian cancer, gastricadenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor,angiosarcoma, and epithelioid hemangioendothelioma (Davies, K. D. etal., Clin Cancer Res 2013, 19 (15): 4040-4045). Targeting ROS1 fusionproteins with crizotinib has demonstrated promising clinical efficacy inNSCLC patients whose tumors are positive for ROS1 genetic abnormalities(Shaw, A. T. et al., N Engl J Med. 2014, 371(21):1963-1971). Acquiredresistant mutations have been observed in crizotinib treatment patients(Awad, M. M. et al., N Engl J Med. 2013, 368(25):2396-2401). It isurgent to develop the second generation of ROS1 inhibitors forovercoming crizotinib ROS1 resistance.

There remains a need for small molecule inhibitors of these multipleprotein or tyrosine kinase targets with desirable pharmaceuticalproperties. Certain diaryl macrocyclic compounds have been found in thecontext of this invention to have this advantageous activity profile.

SUMMARY

In one aspect, the invention relates to a compound of the followingFormula (I-A):

wherein

Ring A′ and Ring B′ are each independently a monocyclic or bicyclic arylor heteroaryl; wherein one of Ring A′ and Ring B′ is a monocyclic arylor heteroaryl and the other is a bicyclic heteroaryl; and at least oneof Ring A′ and Ring B′ comprises at least one nitrogen ring member;

each L¹ and L² is independently —C(R^(1′))(R^(2′))—, —O—, —N(R^(k′))—,—S—, —S(O)— or —S(O)₂—;

each R^(1′) and R^(2′) are independently H, deuterium, halogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl, —OR^(a′),—OC(O)R^(a′), —OC(O)NR^(a′)R^(b′), —OS(O)R^(a′), —OS(O)₂R^(a′),—SR^(a′), —S(O)R^(a′), —S(O)₂R^(a′), —S(O)NR^(a′)R^(b′),—S(O)₂NR^(a′)R^(b′), —OS(O)NR^(a′)R^(b′), —OS(O)₂NR^(a′)R^(b′),—NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)OR^(b′),—NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)S(O)R^(b′), —NR^(a′)S(O)₂R^(b′),—NR^(a′)S(O)NR^(a′)R^(b′), —NR^(a′)S(O)₂NR^(a′)R^(b′), —C(O)R^(a′),—C(O)OR^(a′), —C(O)NR^(a′)R^(b′), —PR^(a′)R^(b′), —P(O)R^(a′)R^(b′),—P(O)₂R^(a′)R^(b′), —P(O)NR^(a′)R^(b′), —P(O)₂NR^(a′)R^(b′),—P(O)OR^(a′), —P(O)₂OR^(a′), —CN, or —NO₂, or R^(1′) and R^(2′) takentogether with the carbon or carbons to which they are attached form aC₃₋₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein eachhydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, mono- or bicyclicheteroaryl, 4- to 6-membered heterocycloalkyl is independentlyoptionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,—OR^(e′), —OC(O)R^(e′), —OC(O)NR^(e′)R^(f′), —OS(O)R^(e′),—OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′), —OS(O)₂NR^(e′)R^(f′), —SR^(e′),—S(O)R^(e′), —S(O)₂R^(e′), —S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′)R^(f′),—NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′),—NR^(e′)C(O)NR^(e′)R^(f′), —NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′),—NR^(e′)S(O)NR^(e′)R^(f′), —NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′),—C(O)OR^(e′), —C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′),—P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′),—P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂;

each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom inC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, —OR^(e′), —OC(O)R^(e′), —OC(O)NR^(e′)R^(f′),—OS(O)R^(e′), —OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′), —OS(O)₂NR^(e′)R^(f′),—SR^(e′), —S(O)R^(e′), —S(O)₂R^(e′), —S(O)NR^(e′)R^(f′),—S(O)₂NR^(e′)R^(f′), —NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′),—NR^(e′)C(O)OR^(f′), —NR^(e′)C(O)NR^(e′)R^(f′), —NR^(e′)S(O)R^(f′),—NR^(e′)S(O)₂R^(f′), —NR^(e′)S(O)NR^(e′)R^(f′),—NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′), —C(O)OR^(e′),—C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′),—P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′),—P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂;

each R^(3′) and R^(4′) is independently deuterium, halogen, —OR^(c′),—OC(O)R^(c′), —OC(O)NR^(c′)R^(d′), —OC(═N)NR^(c′)R^(d′), —OS(O)R^(c′),—OS(O)₂R^(c′), —OS(O)NR^(c′)R^(d′), —OS(O)₂NR^(c′)R^(d′), —SR^(c′),—S(O)R^(c′), —S(O)₂R^(c′), —S(O)NR^(c′)R^(d′), —S(O)₂NR^(c′)R^(d′),—NR^(c′)R^(d′), —NR^(c′)C(O)R^(d′), —NR^(c′)C(O)OR^(d′),—NR^(c′)C(O)NR^(c′)R^(d′), —NR^(c′)C(═N)NR^(c′)R^(d′),—NR^(c′)S(O)R^(d′), —NR^(c′)S(O)₂R^(d′), —NR^(c′)S(O)NR^(c′)R^(d′),—NR^(c′)S(O)₂NR^(c′)R^(d′), —C(O)R^(c′), —C(O)OR^(c′),—C(O)NR^(c′)R^(d′), —C(═N)NR^(c′)R^(d′), —PR^(c′)R^(d′),—P(O)R^(c′)R^(d′), —P(O)₂R^(c′)R^(d′), —P(O)NR^(c′)R^(d′),—P(O)₂NR^(c′)R^(d′), —P(O)OR^(c′), —P(O)₂OR^(c′), —CN, —NO₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl, or anytwo R^(3′) groups or any two R^(4′) groups taken together with the ringto which they are attached form a C₅₋₈cycloalkyl or a 5- to 8-memberedheterocycloalkyl, wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀aryl, mono- or bicyclic heteroaryl C₅₋₈cycloalkyl or a 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(e′), —OC(O)R^(e′),—OC(O)NR^(e′)R^(f′), —OS(O)R^(e′), —OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′),—OS(O)₂NR^(e′)R^(f′), —SR^(e′), —S(O)R^(e′), —S(O)₂R^(e′),—S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′)R^(f′), —NR^(e′)R^(f′),—NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′), —NR^(e′)C(O)NR^(e′)R^(f′),—NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′), —NR^(e′)S(O)NR^(e′)R^(f′),—NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′), —C(O)OR^(e′),—C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′),—P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′),—P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂;

R^(7′) is H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono-or bicyclic heteroaryl, wherein each hydrogen atom in C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(i′),—OC(O)R^(i′), —OC(O)NR^(i′)R^(j′), —OS(O)R^(i′), —OS(O)₂R^(i′),—OS(O)NR^(i′)R^(j′), —OS(O)₂NR^(i′)R^(j′), —SR^(i′), —S(O)R^(i′),—S(O)₂R^(i′), —S(O)NR^(i′)R^(j′), —S(O)₂NR^(i′)R^(j′), —NR^(i′)R^(j′),—NR^(i′)C(O)R^(j′), —NR^(i′)C(O)OR^(j′), —NR^(i′)C(O)NR^(i′)R^(j′),—NR^(i′)S(O)R^(j′), —NR^(i′)S(O)₂R^(j′), —NR^(i′)S(O)NR^(i′)R^(j′),—NR^(i′)S(O)₂NR^(i′)R^(j′), —C(O)R^(i′), —C(O)OR^(i′),—C(O)NR^(i′)R^(j′), —PR^(i′)R^(j′), —P(O)R^(i′)R^(j′),—P(O)₂R^(i′)R^(j′), —P(O)NR^(i′)R^(j′), —P(O)₂NR^(i′)R^(j′),—P(O)OR^(i′), —P(O)₂OR^(i′), —CN, or —NO₂;

each R^(a′), R^(b′), R^(c′), R^(d′), R^(e′), R^(f′), R^(i′) and R^(j′)is independently selected from the group consisting of H, deuterium,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, and heteroaryl;

m′ is 2, 3, 4, or 5;

n′ is 2, 3, or 4;

p′ is 0, 1, 2, 3, or 4; and

q′ is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In one aspect, the invention relates to a chemical entity of thefollowing Formula (I-A):

wherein

Ring A′ and Ring B′ are each independently a monocyclic or bicyclic arylor heteroaryl;

wherein one of Ring A′ and Ring B′ is a monocyclic aryl or heteroaryland the other is a bicyclic heteroaryl; and at least one of Ring A′ andRing B′ comprises at least one nitrogen ring member;

each R^(3′) and R^(4′) is independently deuterium, halogen, —OR^(c′),—OC(O)R^(c′), —OC(O)NR^(c′)R^(d′), —OC(═N)NR^(c′)R^(d′),—OS(O)₀₋₂R^(c′), —OS(O)₀₋₂NR^(c′)R^(d′), —S(O)₀₋₂R^(c′),—S(O)₀₋₂NR^(c′)R^(d′), —NR^(c′)R^(d′), —NR^(c′)C(O)R^(d′),—NR^(c′)C(O)NR^(c′)R^(d′), —NR^(c′)C(═N)NR^(c′)R^(d′),—NR^(c′)S(O)₀₋₂R^(d′), —NR^(c′)S(O)₀₋₂NR^(c′)R^(d′), —C(O)R^(c′),—C(O)OR^(c′), —C(O)NR^(c′)R^(d′), —C(═N)NR^(c′)R^(d′),—P(O)₀₋₂R^(c′)R^(d′), —P(O)₀₋₂NR^(c′)R^(d′), —P(O)₀₋₂OR^(c), —CN, —NO₂,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 7-memberedheterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl; orany two R^(3′) groups or any two R^(4′) groups taken together with thering to which they are attached form a C₅₋₈cycloalkyl or a 5- to8-membered heterocycloalkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, naphthyl, and mono- or bicyclic heteroaryl is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(e′),—OC(O)R^(e′), —OC(O)NR^(e′)R^(f′), —OS(O)₀₋₂R^(e′),—OS(O)₀₋₂NR^(e′)R^(f′), —S(O)₀₋₂R^(e′), —S(O)₀₋₂NR^(e′)R^(f′),—NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′), —NR^(e′)C(O)NR^(e′)R^(f′),—NR^(e′)S(O)₀₋₂R^(f′), —NR^(e′)S(O)₀₋₂NR^(e′)R^(f′), —C(O)R^(e′),—C(O)OR^(e′), —C(O)NR^(e′)R^(f′), —P(O)₀₋₂R^(e′)R^(f′),—P(O)₀₋₂NR^(e′)R^(f′), —P(O)₀₋₂OR^(e′), —CN, and —NO₂; and

each R^(c′), R^(d′), R^(e′), and R^(f′) is independently selected fromthe group consisting of H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl,naphthyl, and heteroaryl;

R^(7′) is H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, ormono- or bicyclic heteroaryl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, naphthyl, or heteroaryl is substituted or unsubstituted with oneor more substituents selected from the group consisting of deuterium,halogen, —OR^(i′), —OC(O)R^(i′), —OC(O)NR^(i′)R^(j′), —OS(O)₀₋₂R^(i′),—OS(O)₀₋₂NR^(i′)R^(j′), —S(O)₀₋₂R^(i′), —S(O)₀₋₂NR^(i′)R^(j′),—NR^(i′)R^(j′), —NR^(i′)C(O)R^(j′), —NR^(i′)C(O)NR^(i′)R^(j′),—NR^(i′)S(O)₀₋₂R^(j′), —NR^(i′)S(O)₀₋₂NR^(i′)R^(j′), —C(O)R^(i′),—C(O)OR^(i′), —C(O)NR^(i′)R^(j′), —P(O)₀₋₂R^(i′)R^(j′),—P(O)₀₋₂NR^(i′)R^(j′), —P(O)₀₋₂OR^(i′), —CN, and —NO₂;

wherein each R^(i′) and R^(j′) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

each L¹ and L² is independently —C(R^(1′))(R^(2′))—, —O—, —N(R^(k′))—,or —S(O)₀₋₂;

wherein each R^(i′) and R^(2′) are independently H, deuterium, halogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl; orR^(i′) and R^(2′) taken together with the carbon or carbons to whichthey are attached form a C₃₋₆cycloalkyl or a 4- to 6-memberedheterocycloalkyl;

each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl,naphthyl, or mono- or bicyclic heteroaryl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, naphthyl, or heteroaryl in R^(i′), R^(2′), or R^(k)′ isindependently unsubstituted or substituted with one or more substituentsselected from the group consisting of deuterium, halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, —OR^(a′), —OC(O)R^(a′), —OC(O)NR^(a′)R^(b′),—OS(O)₀₋₂R^(a′), —OS(O)₀₋₂NR^(a′)R^(b′), —S(O)₀₋₂R^(a′),—S(O)₀₋₂NR^(a′)R^(b′), —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)S(O)₀₋₂R^(b′),—NR^(a′)S(O)₀₋₂NR^(a′)R^(b′), —C(O)R^(a′), —C(O)OR^(a′),—C(O)NR^(a′)R^(b′), —P(O)₀₋₂R^(a′)R^(b′), —P(O)₀₋₂NR^(a′)R^(b′),—P(O)₀₋₂OR^(a′), —CN, and —NO₂;

wherein each R^(a′) and R^(b′) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, phenyl, naphthyl, or heteroaryl;

m′ is 3, 4, or 5;

n′ is 2, 3, or 4;

p′ is 0, 1, 2, 3, or 4; and

q′ is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a chemical entity of thefollowing Formula (I):

wherein

Ring A and Ring B are each independently a monocyclic or bicyclic arylor heteroaryl; wherein one of Ring A and Ring B is monocyclic and theother is bicyclic; and Ring comprises at least one nitrogen ring member;

R¹ and R² are each independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl,naphthyl, or mono- or bicyclic heteroaryl; or R¹ and R² taken togetherwith the carbon to which they are attached form a C₃₋₆cycloalkyl or a 4-to 6-membered heterocycloalkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, naphthyl, or heteroaryl is unsubstituted or substituted with oneor more substituents selected from the group consisting of deuterium,halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(a),—OC(O)R^(a),—OC(O)NR^(a)R^(b), —OS(O)₀₋₂R^(a), —OS(O)₀₋₂NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),—NR^(a)S(O)₀₋₂R^(b), —NR^(a)S(O)₀₋₂NR^(a)R^(b), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —P(O)₀₋₂R^(a)R^(b), —P(O)₀₋₂NR^(a)R^(b),—P(O)₀₋₂OR^(a), —CN, and —NO₂;

wherein each R^(a) and R^(b) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, phenyl, naphthyl, or heteroaryl;

each R³ and R⁴ is independently deuterium, halogen, —OR^(c),—OC(O)R^(c), —OC(O)NR^(c)R^(d), —OC(═N)NR^(c)R^(d), —OS(O)₀₋₂R^(c),—OS(O)₀₋₂NR^(c)R^(d), —NR^(c)R^(d), —NR^(c)C(O)R^(d),—NR^(c)C(O)NR^(c)R^(d), —NR^(c)C(═N)NR^(c)R^(d), —NR^(c)S(O)₀₋₂R^(d),—NR^(c)S(O)₀₋₂NR^(c)R^(d), —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d),—C(═N)NR^(c)R^(d), —P(O)₀₋₂R^(c)R^(d), —P(O)₀₋₂NR^(c)R^(d),—P(O)₀₋₂OR^(c), —CN, —NO₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, ormono- or bicyclic heteroaryl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, naphthyl, and mono- or bicyclic heteroaryl is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OS(O)₀₋₂R^(e), —OS(O)₀₋₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)NR^(e)R^(f),—NR^(e)S(O)₀₋₂R^(f), —NR^(e)S(O)₀₋₂NR^(e)R^(f), —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(e)R^(f), —P(O)₀₋₂R^(e)R^(f), —P(O)₀₋₂NR^(e)R^(f),—P(O)₀₋₂OR^(e), —CN, and —NO₂; and

each R^(c), R^(d), R^(e), and R^(f) is independently selected from thegroup consisting of H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, andheteroaryl;

R⁵ and R⁶ are each independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl,naphthyl, or mono- or bicyclic heteroaryl; or R⁵ and R⁶ taken togetherwith the carbon to which they are attached form a C₃₋₆cycloalkyl or a 4-to 6-membered heterocycloalkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, naphthyl, or heteroaryl is substituted or unsubstituted with oneor more substituents selected from the group consisting of deuterium,halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(g), —OC(O)R^(g),—OC(O)NR^(g)R^(h), —OS(O)₀₋₂R^(g), —OS(O)₀₋₂NR^(g)R^(h), —NR^(g)R^(h),—NR^(g)C(O)R^(h), —NR^(g)C(O)NR^(g)R^(h), —NR^(g)S(O)₀₋₂R^(h),—NR^(g)S(O)₀₋₂NR^(g)R^(h), —C(O)R^(g), —C(O)OR^(g), —C(O)NR^(g)R^(h),—P(O)₀₋₂R^(g)R^(h), —P(O)₀₋₂NR^(g)R^(h), —P(O)₀₋₂₀R^(g), —CN, and —NO₂;

wherein each R^(g) and R^(h) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

R⁷ is H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- orbicyclic heteroaryl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,phenyl, naphthyl, or heteroaryl is substituted or unsubstituted with oneor more substituents selected from the group consisting of deuterium,halogen, —OR^(i), —OC(O)R^(i), —OC(O)NR^(i)R^(j), —OS(O)₀₋₂R^(i),—OS(O)₀₋₂NR^(i)R^(j), —NR^(i)R^(j), —NR^(i)C(O)R^(j),—NR^(i)C(O)NR^(i)R^(j), —NR^(i)S(O)₀₋₂R^(j), —NR^(i)S(O)₀₋₂NR^(i)R^(j),—C(O)R^(i), —C(O)OR^(i), —C(O)NR^(i)R^(j), —P(O)₀₋₂R^(i)R^(j),—P(O)₀₋₂NR^(i)R^(j), —P(O)₀₋₂OR^(i), —CN, and —NO₂;

wherein each R^(i) and R^(j) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

X and Y are each independently —C(R^(k))(R^(k))—, —O—, or —N(R^(k))—;

wherein each R^(k) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

m is 2, 3, or 4;

n is 1, 2, or 3;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) or (I-A) is acompound selected from those species described or exemplified in thedetailed description below.

In certain embodiments, the compound of Formula (I) or (I-A) is acompound having the formula

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) or (I-A) is acompound having the formula

or a pharmaceutically acceptable salt thereof

In certain embodiments, the compound of Formula (I) or (I-A) is acompound the formula

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) or (I-A) is acompound having the formula

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) or (I-A) is acompound having the formula

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) or (I-A) is acompound having the formula

or a pharmaceutically acceptable salt thereof.

In a further aspect, the invention relates to a crystalline form of thefree base of the compound of the formula

having a powder X-ray diffraction pattern substantially the same as FIG.XX. In some embodiments, the crystalline polymorph form 1 of the freebase of the compound of the formula

wherein the powder X-ray diffraction pattern has a peak at diffractionangle (2θ) of 21.94. In some embodiments, the polymorph form 1 of thefree base of the compound of the formula

wherein the powder X-ray diffraction pattern has peaks at diffractionangles (2θ) of 21.94 and 23.96. In some embodiments, the polymorph form1 of the free base of the compound of the formula

wherein the powder X-ray diffraction pattern has peaks at diffractionangles (2θ) of 21.94, 23.96 and 19.64.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising at least one compound of Formula (I) or (I-A) ora pharmaceutically acceptable salt thereof. Pharmaceutical compositionsaccording to the invention may further comprise a pharmaceuticallyacceptable excipient. The invention is also a compound of Formula (I) or(I-A) or a pharmaceutically acceptable salt thereof for use as amedicament.

In another aspect, the invention is directed to a method of treatingcancer, pain, neurological diseases, autoimmune diseases, orinflammation comprising administering to a subject in need of suchtreatment an effective amount of at least one compound of Formula (I) or(I-A) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention is directed to use of a compound ofFormula (I) or (I-A) in the preparation of a medicament for thetreatment of such diseases and medical conditions, and the use of suchcompounds and salts for treatment of such diseases and medicalconditions.

In yet another aspect, the invention relates to a method of inhibitingprotein or tyrosine kinases, including one or more of MET, ALK, ROS1,AXL, TRKs, and JAKs, comprising contacting a cell comprising one or moreof such kinases with an effective amount of at least one compound ofFormula (I) or (I-A) or a salt thereof, and/or with at least onepharmaceutical composition of the invention, wherein the contacting isin vitro, ex vivo, or in vivo.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

For the sake of brevity, the disclosures of the publications cited inthis specification, including patents, are herein incorporated byreference.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of the crystallinepolymorph form 1 of the free base of11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclo-tridecin-4(5H)-one(Example 20).

FIG. 2 shows a differential scanning calorimetry thermogram of thecrystalline polymorph form 1 of the free base of11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclo-tridecin-4(5H)-one(Example 20).

DETAILED DESCRIPTION

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. All patents, applications,published applications and other publications referred to herein areincorporated by reference in their entireties. If a definition set forthin this section is contrary to or otherwise inconsistent with adefinition set forth in a patent, application, or other publication thatis herein incorporated by reference, the definition set forth in thissection prevails over the definition incorporated herein by reference.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. It is further noted that the claims may be drafted to excludeany optional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely,”“only” and the like in connection with the recitation of claim elements,or use of a “negative” limitation.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001.

Chemical nomenclature for compounds described herein has generally beenderived using the commercially-available ACD/Name 2014 (ACD/Labs) orChemBioDraw Ultra 13.0 (Perkin Elmer).

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present invention and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace compounds thatare stable compounds (i.e., compounds that can be isolated,characterized, and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables are also specifically embraced by the presentinvention and are disclosed herein just as if each and every suchsub-combination of chemical groups was individually and explicitlydisclosed herein.

CHEMICAL DEFINITIONS

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “alkenyl” refers to a straight- or branched-chain hydrocarbongroup having from 2 to 12 carbon atoms in the chain, and having one ormore double bonds. Examples of alkenyl groups include ethenyl (orvinyl), allyl, and but-3-en-1-yl. Included within this term are cis andtrans isomers and mixtures thereof.

The term “alkynyl” refers to a straight- or branched-chain hydrocarbongroup having from 2 to 12 carbon atoms in the chain, and having one ormore triple bonds. Examples of alkynyl groups include acetylenyl (—C≡CH)and propargyl (—CH₂C≡CH).

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic or polycyclic carbocycle having 3 to 12 ring atoms.Polycyclic carbocycles include fused, bridged, and spiro polycyclicsystems. Illustrative examples of cycloalkyl groups include thefollowing entities, in the form of properly bonded moieties:

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl group with one or more halosubstituents, or one, two, or three halo substituents. Examples ofhaloalkyl groups include CF₃, —(CH₂)F, —CHF₂, —CH₂Br, —CH₂CF₃, andCH₂CH₂F.

The term “aryl” refers to an all-carbon monocyclic or fused-ringpolycyclic groups of 6 to 14 carbon atoms (C₆-C₁₄) having a completelyconjugated pi-electron system. Aryl includes all-carbon monocyclic orfused-ring polycyclic groups of 6 to 10 carbon atoms (e.g. “C₆₋₁₀aryl”). Examples, without limitation, of aryl groups are phenyl,naphthalenyl and anthracenyl. The aryl group may be substituted asdescribed above for alkyl or unsubstituted. Substituent groups alsoinclude those described elsewhere in this disclosure in connection witharyl.

The term “heterocycloalkyl” refers to a monocyclic or polycyclic ringstructure that is saturated or partially saturated and has from 3 to 12ring atoms, with 1 to 5 of the ring atoms selected from nitrogen,oxygen, and sulfur. Polycyclic ring systems include fused, bridged, andSpiro systems. The ring structure may optionally contain up to two oxogroups on carbon or sulfur ring members. Illustrative examples ofheterocycloalkyl groups include the following entities, in the form ofproperly bonded moieties:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atoms ormembers selected from carbon atoms and up to four heteroatoms selectedfrom nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

A “monocyclic” heteroaryl is an aromatic five- or six-memberedheterocycle. A five-membered heteroaryl contains up to four heteroatomring atoms, where (a) one ring atom is oxygen and sulfur and zero, one,or two ring atom is nitrogen, or (b) zero ring atoms are oxygen orsulfur and up to four ring atoms are nitrogen. In some embodiments, afive-membered heteroaryl is furan, thiophene, pyrrole, oxazole,isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole,thiadiazole, triazole, or tetrazole. A six-membered heteroaryl containsone or two nitrogen ring atoms. In some embodiments, a six-memberedheteroaryl is pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A“bicyclic heteroaryl” is a fused bicyclic system comprising oneheteroaryl ring fused to a phenyl or another heteroaryl ring.

The term “oxo” represents a carbonyl oxygen. For example, a cyclopentylsubstituted with oxo is cyclopentanone.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. Where the term “substituted” isused to describe a structural system, the substitution is meant to occurat any valency-allowed position on the system. In some embodiments,“substituted” means that the specified group or moiety bears one, two,or three substituents. In other embodiments, “substituted” means thatthe specified group or moiety bears one or two substituents. In stillother embodiments, “substituted” means the specified group or moietybears one substituent.

Any formula depicted herein is intended to represent a compound of thatstructural formula as well as certain variations or forms. For example,a formula given herein is intended to include a racemic form, or one ormore enantiomeric, diastereomeric, or geometric isomers, or a mixturethereof. Additionally, any formula given herein is intended to referalso to a hydrate, solvate, or polymorph of such a compound, or amixture thereof.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I respectively. Such isotopically labelled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Further,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements. Isotopically labeled compounds of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

The nomenclature “(ATOM)_(i-j)” with j>i, when applied herein to a classof substituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of atom members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

The invention also includes pharmaceutically acceptable salts of thecompounds represented by Formula (I) or (I-A), preferably of thosedescribed above and of the specific compounds exemplified herein, andpharmaceutical compositions comprising such salts, and methods of usingsuch salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented herein that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferredpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of subjects withoutundue toxicity, irritation, or allergic response. A compound describedherein may possess a sufficiently acidic group, a sufficiently basicgroup, both types of functional groups, or more than one of each type,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,methylsulfonates, propylsulfonates, besylates, xylenesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates,phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists ofother suitable pharmaceutically acceptable salts are found inRemington's Pharmaceutical Sciences, 17th Edition, Mack PublishingCompany, Easton, Pa., 1985.

For a compound of Formula (I) or (I-A) that contains a basic nitrogen, apharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, or ethanesulfonic acid, or any compatible mixtureof acids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I) or (I-A), and treatment methods employingsuch pharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I) or (I-A)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula (I) or (I-A), and uses of suchmetabolites in the methods of the invention. A “pharmaceutically activemetabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or (I-A) or salt thereof. Prodrugsand active metabolites of a compound may be determined using routinetechniques known or available in the art. See, e.g., Bertolini et al.,J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv.Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (ElsevierPress, 1985); and Larsen, Design and Application of Prodrugs, DrugDesign and Development (Krogsgaard-Larsen et al., eds., Harwood AcademicPublishers, 1991).

REPRESENTATIVE EMBODIMENTS

In some embodiments of Formula (I-A), Ring A′ is monocyclic aryl orheteroaryl and Ring B′ is bicyclic heteroaryl. In other embodiments,Ring A′ is bicyclic heteroaryl and Ring B′ is monocyclic aryl orheteroaryl. In some embodiments, Ring A′ is phenyl or a 6-memberedheteroaryl. In other embodiments, Ring B′ is bicyclic heteroarylcontaining 1, 2, or 3 nitrogen ring atoms. In other embodiments, Ring A′is phenyl or pyridyl.

In still other embodiments, Ring A′ is phenyl. In still otherembodiments, Ring A′ substituted with —(R^(3′))_(p′) is

In still other embodiments, Ring A′ substituted with —(R^(3′))_(p′) is

In some embodiments, Ring B′ is:

wherein Z¹—Z⁷ are defined as described herein. In still otherembodiments, Ring B′ is:

wherein Z¹⁻⁷ are otherwise defined as described herein. In still otherembodiments, Ring B′ is:

In still other embodiments, Ring B′ is

In still other embodiments, Ring B′ is

In other embodiments of Formula (I-A), Ring A′ is a bicyclic heteroarylgroup, and is:

wherein Z¹—Z⁷ are defined as described herein. In still otherembodiments, Ring A′ is:

wherein Z¹⁻⁷ are otherwise defined as described herein. In still otherembodiments, Ring A′ is:

In still other embodiments, Ring A′ is

In still other embodiments, Ring A′ is

In some embodiments, Ring B′ is the monocyclic aryl or heteroaryl. Inother embodiments, Ring B′ is phenyl. In other embodiments, Ring B′ ispyridyl.

In some embodiments, each R^(3′) is independently deuterium, fluoro,chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,isopropoxy, —CN, —CF₃, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—CO₂C₁₋₄alkyl, —CO₂H, —NHC(O)C₁₋₄alkyl, —SO₂C₁₋₄alkyl, —C(O)NH₂,—C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)₂, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl. In still other embodiments, each R^(3′)is independently fluoro, chloro, bromo, methyl, ethyl, propyl,isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF₃. In still otherembodiments, each R^(3′) is fluoro or chloro.

In some embodiments, R⁷ is H, deuterium, methyl, ethyl, propyl,isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl,thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, ormonocyclic heteroaryl, each substituted or unsubstituted as in Formula(I-A). In other embodiments, R⁷ is H, or is methyl, ethyl, propyl,isopropyl, or cyclopropyl, each unsubstituted or substituted as inFormula (I-A). In still other embodiments, R⁷ is H or is methyl orethyl, each unsubstituted or substituted with halogen, —OH, —OC₁₋₄alkyl,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,cycloalkyl, or monocyclic heterocycloalkyl. In still other embodiments,R⁷ is H, methyl, hydroxyethyl, —CH₂CONH₂, or 3-pyrrolidinylmethyl. Instill other embodiments, R⁷ is H or methyl.

In some embodiments, R^(1′) and R^(2′) are each independently H,deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl,piperazinyl, morpholinyl, phenyl, or monocyclic heteroaryl, eachsubstituted or unsubstituted as in Formula (I-A). In other embodiments,R^(1′) is H. In still other embodiments, R^(2′) is deuterium, methyl,ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl,morpholinyl, phenyl, or monocyclic heteroaryl, each substituted orunsubstituted as in Formula (I-A). In still other embodiments, R^(2′) isH or is methyl or ethyl, each unsubstituted or substituted with halogen,—OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H,—CO₂C₁₋₄alkyl, —CONH₂, cycloalkyl, or monocyclic heterocycloalkyl. Instill other embodiments, R^(2′) is H, methyl, fluoromethyl,hydroxymethyl or cyclopropyl. In still other embodiments, R^(2′) is H.In still other embodiments, R^(2′) is methyl.

In some embodiments, each R^(k′) is independently H, methyl, ethyl,propyl, isopropyl, or cyclopropyl. In other embodiments, each R^(k′) isindependently H or methyl.

In some embodiments, each L¹ and L² is independently —CH₂— or—CH(methyl)-, —CH(substituted methyl)-, —CH(C₃₋₆cyclopropyl)-, —CH(OH)—,—O—, —NH—, —N(C₁₋₄alkyl)-, —N(C₃₋₆cyclopropyl)-, —S—, —S(O)—, or —SO₂—.In some embodiments, -(L¹)_(n′)- is —CH₂—O—, —CH(C₁₋₄alkyl)-O—, or—CH(C₃₋₆cycloalkyl)-O—. In other embodiments, -(L¹)_(n′)- is —CH(H oroptionally substituted C₁₋₄alkyl)-N(H or optionally substitutedC₁₋₄alkyl)-, —CH(CO₂C₁₋₄alkyl or C(O)N(H or C₁₋₄alkyl)₂)-N(H oroptionally substituted C₁₋₄alkyl). In still other embodiments,-(L¹)_(n′)- is —CH₂S(O)₀₋₂—. In other embodiments, -(L¹)_(n′)- is—SO₂—N(H or C₁₋₄alkyl). In some embodiments, -(L¹)_(n′)- is —(CH₂)₃—. Insome embodiments, -(L¹)_(n′)- is —(CH₂)₂—. In some embodiments,-(L¹)_(n′)- is —CH(CH₃)CH₂—.

In some embodiments, -(L²)_(m′) is —O—(C(R^(1′)) (R^(2′)))₂₋₃—. In otherembodiments, -(L²)_(m′) is —O—(CH₂)₂₋₃—. In other embodiments,-(L²)_(m′) is —N(R^(k′))—(C(R^(1′))(R^(2′)))₂₋₃—. In other embodiments,-(L²)_(m′) is —N(H or C₁₋₄alkyl)-(CH₂)₂₋₃—. In other embodiments,-(L²)_(m′) is —S—(C(R^(1′))(R^(2′)))₂₋₃—. In other embodiments,-(L²)_(m′) is —SO₂—(C(R^(1′))(R^(2′)))₂₋₃—. In still other embodiments,-(L²)_(m′) is —SO₂—N(R^(k′))—(C(R^(1′))(R^(2′)))₂₋₃—. In still otherembodiments, -(L²)_(m′) is —(C(R^(1′))(R^(2′)))₃—.

In some embodiments, m′ is 3. In other embodiments, m′ is 4. In stillother embodiments, m′ is 5. In some embodiments, n′ is 2. In otherembodiments, n′ is 3. In still other embodiments, n′ is 4. In someembodiments, p′ is 0, 1, or 2. In other embodiments, p′ is 1 or 2. Insome embodiments, q′ is 0. In other embodiments, q′ is 1. In still otherembodiments, q′ is 2.

In some embodiments of Formula (I-A) are compounds of Formula (I), orpharmaceutically acceptable salts thereof. In other embodiments,compounds of Formula (I-A) are compounds of Formula (I), wherein eachvariable is independently defined as indicated below for Formula (I). Insome embodiments, the variables of Formula (I-A) map onto Formula (I) asfollows: A′ is A; B′ is B; R^(1′) is R¹; R^(2′) is R²; R^(3′) is R³;R^(4′) is R⁴; R^(7′) is R⁷; R^(a′)—R^(f′) and R^(i′)—R^(k′) map ontoR^(a)—R^(f) and R^(i)—R^(k), respectively; and L¹ and L² are—Y—(C(R⁵)(R⁶))_(m)— and —C((R¹)(R²))_(n)—X—, respectively.

In some embodiments of Formula (I), Ring A is phenyl or a 6-memberedheteroaryl. In other embodiments, Ring A is phenyl or pyridyl. In stillother embodiments, Ring A is phenyl. In still other embodiments, Ring Asubstituted with 4R³)_(p) is

In still other embodiments, Ring A substituted with 4R³)_(p) is

In some embodiments, each R³ is independently deuterium, fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,—CN, —CF₃, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂C₁₋₄alkyl, —CO₂H,—NHC(O)C₁₋₄alkyl, —SO₂C₁₋₄alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl),—C(O)N(C₁₋₄alkyl)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.In still other embodiments, each R³ is independently fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,—CN, or —CF₃. In still other embodiments, each R³ is fluoro or chloro.

In still other embodiments, Ring A substituted with —(R³)_(p) is

where R^(3a) and R^(3b) are each independently H, fluoro, or chloro andM is CH or N. In some embodiments, R^(3a) is fluoro.

In some embodiments, p is 1 or 2. In other embodiments, p is zero. Instill other embodiments, p is 1. In still other embodiments, p is 2.

In some embodiments, Ring B is a bicyclic heteroaryl. In otherembodiments, Ring B is a 9-membered bicyclic heteroaryl.

In some embodiments, each R⁴ is independently deuterium, fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,—CN, —CF₃, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂C₁₋₄alkyl, —CO₂H,—NHC(O)C₁₋₄alkyl, —SO₂C₁₋₄alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl),—C(O)N(C₁₋₄alkyl)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.In still other embodiments, each R⁴ is independently fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,—CN, or —CF₃.

In other embodiments, Ring B substituted with —(R⁴)_(q) is:

wherein Z¹, Z², Z³, and Z⁶ are each independently —C(R^(x))— or N;

wherein each R^(x) is independently H, deuterium, halogen, C₁₋₄alkyl,—O—C₁₋₄alkyl, —OH, —NH₂, —NHC₁₋₄alkyl, —NH-phenyl, —NH-heteroaryl, CN,or —CF₃;

Z⁴ and Z⁵ are each independently —C— or —N—; and

Z⁷ is —CH—, —N—, or —NH—;

In other embodiments:

(a) Z¹, Z⁴, and Z⁷ are each —N—;

(b) Z¹, Z⁵, and Z⁷ are each —N—;

(c) Z¹ and Z³ are —N— and Z⁷ is —NH—;

(d) Z³ is —N— and Z⁷ is —NH—;

(e) Z³ and Z⁶ are each —N— and Z⁷ is —NH—;

(f) Z², Z⁴, and Z⁷ are each —N—;

(g) Z¹, Z², Z⁴, and Z⁷ are each —N—;

(h) Z¹, Z³, and Z⁴ are each —N—;

(i) Z³ and Z⁴ are each —N—;

(j) Z¹, Z², Z⁵, and Z⁷ are each —N—;

(k) Z², Z⁵, and Z⁷ are each —N—;

(1) Z³ and Z⁵ are each —N—;

(m) Z³, Z⁵, and Z⁶ are each —N—;

(n) Z¹, Z⁵, Z⁶, and Z⁷ are each —N—;

(o) Z², Z⁵, Z⁶, and Z⁷ are each —N—; or

(p) Z¹, Z³, and Z⁶ are each —N— and Z⁷ is —NH—.

In still other embodiments of (a)-(p), each Z ring atom that is notdefined expressly is independently —C— or —C(R^(x))— (consistently withthe definition of such ring atom). In still other embodiments, Z³ is—N—. In other embodiment, Z⁷ is —N— or —NH—. In still other embodiments,Z³ is —N— and Z⁷ is —N— or —NH—. In still other embodiments, Ring Bsubstituted with —(R⁴)_(q) is:

wherein Z¹⁻⁷ are otherwise defined as above.

In still other embodiments, Ring B substituted with —(R⁴)_(q) is:

In still other embodiments, Ring B substituted with —(R⁴)_(q) is

In still other embodiments, Ring B substituted with —(R⁴)_(q) is

In some embodiments, q is 0. In other embodiments, q is 1.

In some embodiments, R¹ and R² are each independently H, deuterium,methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl,morpholinyl, phenyl, or monocyclic heteroaryl, each substituted orunsubstituted as in Formula (I). In other embodiments, R¹ is H. In stillother embodiments, R² is deuterium, methyl, ethyl, propyl, isopropyl,cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl,thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, ormonocyclic heteroaryl, each substituted or unsubstituted as in Formula(I). In still other embodiments, R² is H or is methyl or ethyl, eachunsubstituted or substituted with halogen, —OH, —OC₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,cycloalkyl, or monocyclic heterocycloalkyl. In still other embodiments,R² is H, methyl, fluoromethyl, hydroxymethyl or cyclopropyl. In stillother embodiments, R² is H. In still other embodiments, R² is methyl. Instill other embodiments, R¹ is H, and R² is not H and is in thestereochemical configuration shown below:

In still other embodiments, R¹ and R² are taken together to form aC₃₋₆cycloalkyl. In other embodiments, R¹ and R² are taken together toform a 5- or 6-membered heterocycloalkyl, optionally substituted withC₁₋₄alkyl.

In some embodiments, n is 1 or 2. In still other embodiments, n is 1.

In some embodiments, R⁵ and R⁶ are each independently H, deuterium,methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl,morpholinyl, phenyl, or monocyclic heteroaryl, each substituted orunsubstituted as in Formula (I). In other embodiments, each R⁵ is H. Instill other embodiments, each R⁶ is independently H, or is methyl,ethyl, or cyclopropyl, each substituted or unsubstituted as in Formula(I). In still other embodiments, each R⁶ is independently H or methyl,unsubstituted or substituted with OH. In still other embodiments, eachR⁶ is H or methyl. In still other embodiments, R⁵ and R⁶ are takentogether to form a C₃₋₆cycloalkyl. In other embodiments, R⁵ and R⁶ aretaken together to form a 5- or 6-membered heterocycloalkyl, optionallysubstituted with C₁₋₄alkyl.

In some embodiments, m is 2 or 3. In other embodiments, m is 2.

In some embodiments, R⁷ is H, deuterium, methyl, ethyl, propyl,isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl,thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, ormonocyclic heteroaryl, each substituted or unsubstituted as in Formula(I). In other embodiments, R⁷ is H, or is methyl, ethyl, propyl,isopropyl, or cyclopropyl, each unsubstituted or substituted as inFormula (I). In still other embodiments, R⁷ is H or is methyl or ethyl,each unsubstituted or substituted with halogen, —OH, —OC₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,cycloalkyl, or monocyclic heterocycloalkyl. In still other embodiments,R⁷ is H, methyl, hydroxyethyl, —CH₂CONH₂, or 3-pyrrolidinylmethyl. Instill other embodiments, R⁷ is H or methyl.

In some embodiments, each of X and Y is independently —O— or —N(R^(k))—.In some embodiments, X is —O— or —N(R^(k))—. In some embodiments, Y is—O—. In some embodiments, each R^(k) is independently H, methyl, ethyl,propyl, isopropyl, or cyclopropyl. In other embodiments, each R^(k) isindependently H or methyl.

In some embodiments, compounds of Formula (I) or (I-A) are compounds ofFormula (II):

wherein M, R³, q, R², X, R⁷, and Z¹⁻⁷ are each as defined in any of theseveral ways recited above;

R^(5a), R^(5b), R^(6a), and R^(6b) are each R⁵ and R⁶ as defined in anyof the several ways recited above;

or a pharmaceutically acceptable salt thereof.

In some embodiments, compounds of Formula (I) or (I-A) are compounds ofFormula (III):

wherein

M is CH or N;

R^(3a) and R^(3b) are each independently H, fluoro, chloro, bromo,methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or—CF₃;

R^(2a) is H or is methyl or ethyl, each unsubstituted or substitutedwith halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, cycloalkyl, or monocyclicheterocycloalkyl;

X¹ is O or —N(CH₃)—;

R^(5a), R^(6a), R^(5b), and R^(6b) are each independently H, or methylor ethyl, each unsubstituted or substituted with halogen, —OH,—OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl,—CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, cycloalkyl, or monocyclicheterocycloalkyl;

R^(7a) is H or is methyl or ethyl, each unsubstituted or substitutedwith halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂,cycloalkyl, or monocyclic heterocycloalkyl;

Z¹⁻⁷ are each as defined in any of the several ways recited above;

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (III), M is CH.

In other embodiments, R^(3a) and R^(3b) are each independently H,fluoro, or chloro. In still other embodiments, R^(3a) is H or fluoro. Instill other embodiments, R^(3a) is fluoro. In still other embodiments,R^(3b) is H or chloro.

In some embodiments of Formula (III), R^(2a) is H, methyl, fluoromethyl,or cyclopropyl.

In some embodiments or Formula (III), X¹ is O. In other embodiments, Xis —N(CH₃)—.

In some embodiments, R^(7a) is H, methyl, hydroxyethyl, —CH₂CONH₂, or3-pyrrolidinylmethyl. In other embodiments, R^(7a) is H or methyl.

In some embodiments, compounds of Formula (I) or (I-A) are compounds ofFormula (IV):

wherein

M is CH or N;

X¹ and X¹′ are independently —C(R^(1a))(R^(2a))—, —S—, —S(O)—, —S(O)₂—,—O— or —N(R^(k′))—;

each R^(1a) and R^(2a) is independently H, deuterium, C₁₋₆alkyl,C₃₋₆cycloalkyl, C₆₋₁₀ aryl, —C(O)OR^(a′), —C(O)NR^(a′)R^(b′),—NR^(a′)R^(b′), —SR^(a′), —S(O)R^(a′), —S(O)NR^(a′), —S(O)₂R^(a′),—S(O)₂NR^(a′) or —OR^(a′) wherein each hydrogen atom in C₁₋₆alkyl isindependently optionally substituted by deuterium, halogen, —OH,—OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, NHC(O)C₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)C₁₋₄alkyl, —NHC(O)NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)NHC₁₋₄alkyl, NHC(O)N(C₁₋₄alkyl)₂,—N(C₁₋₄alkyl)C(O)N(C₁₋₄alkyl)₂, —NHC(O)OC₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)OC₁₋₄alkyl, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl,—S(O)₂C₁₋₄alkyl, —S(O)NH(C₁₋₄alkyl), —S(O)₂NH(C₁₋₄alkyl),—S(O)N(C₁₋₄alkyl)₂, —S(O)₂N(C₁₋₄alkyl)₂, C₃₋₆cycloalkyl, or 3- to7-membered heterocycloalkyl;

R^(3a) and R^(3b) are each independently H, deuterium, fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,—CN, or —CF₃;

R^(7a) is H, C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl, whereineach hydrogen atom in C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by deuterium, halogen, —CN, —OH,—OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl,—CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, cycloalkyl, or monocyclicheterocycloalkyl;

each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀aryl, or mono- or bicyclic heteroaryl;

wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono-or bicyclic heteroaryl in R^(k)′ is independently optionally substitutedby deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl or —OR^(a′);

wherein each R^(a′) and R^(b′) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or heteroaryl;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R^(x)),wherein each R^(x) when present is independently H, deuterium, halogen,C₁₋₄alkyl, —O—C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —NH(phenyl),—NH(heteroaryl), CN, or —CF₃, provided that at least one of Z¹, Z², Z³,Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH; and

m′ is 2 or 3;

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z¹, Z⁴ and Z⁷ are N, and Z², Z³, Z⁵ and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z¹and Z³ are N, Z⁷ is NH and Z², Z⁴, Z⁵, and Z⁶ are C(R^(x)), wherein eachR^(x) when present is H. In some embodiments, Z¹, Z³ and Z⁶ are N, Z⁷ isNH and Z², Z⁴ and Z⁵ are C(R^(x)), wherein each R^(x) when present is H.In some embodiments, Z³ is N, Z⁷ is NH and Z¹, Z², Z⁴, Z⁵, and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z³and Z⁶ are N, Z⁷ is NH and Z¹, Z², Z⁴ and Z⁵ are C(R^(x)), wherein eachR^(x) when present is H. In some embodiments, Z², Z⁴ and Z⁷ are N andZ¹, Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. Insome embodiments, Z¹, Z⁵ and Z⁷ are N and Z², Z³, Z⁴ and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z¹,Z², Z⁴ and Z⁷ are N and Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x)when present is H. In some embodiments, Z¹, Z², Z⁵ and Z⁷ are N and Z³,Z⁴ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z³, Z⁵ and Z⁶ are N and Z¹, Z², Z⁴ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z¹, Z⁵, Z⁶and Z⁷ are N and Z², Z³ and Z⁴ are C(R^(x)), wherein each R^(x) whenpresent is H. In some embodiments, Z¹, Z² and Z⁴ are N and Z³, Z⁵, Z⁶and Z⁷ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z¹, Z³ and Z⁴ are N and Z², Z⁵, Z⁶ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z³ and Z⁴ areN and Z¹, Z², Z⁵, Z⁶ and Z⁷ are C(R^(x)), wherein each R^(x) whenpresent is H. In some embodiments, Z², Z⁵ and Z⁷ are N and Z¹, Z³, Z⁴and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z³ and Z⁵ are N and Z¹, Z², Z⁴, Z⁶ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z², Z⁵, Z⁶and Z⁷ are N and Z¹, Z³ and Z⁴ are C(R^(x)), wherein each R^(x) whenpresent is H.

In some embodiments, R^(k′) is selected from the group consisting of H,methyl, ethyl, propyl, iso-propyl, cyclopropyl, 2-hydroxyethyl,2-hydroxy-2-methyl-propyl, and N-methyl-pyrrol-3-yl. In someembodiments, M is CH. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N,and Z², Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present isH. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N, Z², Z³, Z⁵ and Z⁶are C(R^(x)), wherein each R^(x) when present is H, and X¹ is—N(R^(k′))—. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N, Z², Z³,Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H, X¹ is—N(R^(k′))—, and X¹′ is —O—. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷are N, Z², Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when presentis H, X¹ is —C(R^(1a))(R^(2a))—, and X¹′ is —O—.

In some embodiments, compounds of Formula (I) or (I-A) are compounds ofFormula (V):

wherein

M is CH or N;

X¹ and X¹′ are independently —C(R^(1a))(R^(2a))—, —S—, —S(O)—, —S(O)₂—,—O— or —N(R^(k′))—;

each R^(1a) and R^(2a) is independently H, deuterium, C₁₋₆alkyl,C₃₋₆cycloalkyl, C₆₋₁₀ aryl, —C(O)OR^(a′), —C(O)NR^(a′)R^(b′),—NR^(a′)R^(b′), —SR^(a′), —S(O)R^(a′), —S(O)NR^(a′), —S(O)₂R^(a′),—S(O)₂NR^(a′) or —OR^(a′) wherein each hydrogen atom in C₁₋₆alkyl isindependently optionally substituted by deuterium, halogen, —OH,—OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, NHC(O)C₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)C₁₋₄alkyl, —NHC(O)NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)NHC₁₋₄alkyl, NHC(O)N(C₁₋₄alkyl)₂,—N(C₁₋₄alkyl)C(O)N(C₁₋₄alkyl)₂, —NHC(O)OC₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)OC₁₋₄alkyl, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl,—S(O)₂C₁₋₄alkyl, —S(O)NH(C₁₋₄alkyl), —S(O)₂NH(C₁₋₄alkyl),—S(O)N(C₁₋₄alkyl)₂, —S(O)₂N(C₁₋₄alkyl)₂, C₃₋₆cycloalkyl, or 3- to7-membered heterocycloalkyl;

R^(3a) and R^(3b) are each independently H, fluoro, chloro, bromo,methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or—CF₃;

R^(7a) is H, C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl, whereineach hydrogen atom in C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —OC₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, cycloalkyl, or monocyclicheterocycloalkyl;

each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl in R^(k)′is independently optionally substituted by deuterium, halogen,C₁₋₆alkyl, C₁₋₆haloalkyl or —OR^(a′);

wherein each R^(a′) and R^(b′) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or heteroaryl;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R^(x)),wherein each R^(x) when present is independently H, deuterium, halogen,C₁₋₄alkyl, —O—C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —NH(phenyl),—NH(heteroaryl), CN, or —CF₃, provided that at least one of Z¹, Z², Z³,Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH; and

m′ is 2 or 3;

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z¹, Z⁴ and Z⁷ are N, and Z², Z³, Z⁵ and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z¹and Z³ are N, Z⁷ is NH and Z², Z⁴, Z⁵, and Z⁶ are C(R^(x)), wherein eachR^(x) when present is H. In some embodiments, Z¹, Z³ and Z⁶ are N, Z⁷ isNH and Z², Z⁴ and Z⁵ are C(R^(x)), wherein each R^(x) when present is H.In some embodiments, Z³ is N, Z⁷ is NH and Z¹, Z², Z⁴, Z⁵, and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z³and Z⁶ are N, Z⁷ is NH and Z¹, Z², Z⁴ and Z⁵ are C(R^(x)), wherein eachR^(x) when present is H. In some embodiments, Z², Z⁴ and Z⁷ are N andZ¹, Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. Insome embodiments, Z¹, Z⁵ and Z⁷ are N and Z², Z³, Z⁴ and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z¹,Z², Z⁴ and Z⁷ are N and Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x)when present is H. In some embodiments, Z¹, Z², Z⁵ and Z⁷ are N and Z³,Z⁴ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z³, Z⁵ and Z⁶ are N and Z¹, Z², Z⁴ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z¹, Z⁵, Z⁶and Z⁷ are N and Z², Z³ and Z⁴ are C(R^(x)), wherein each R^(x) whenpresent is H. In some embodiments, Z¹, Z² and Z⁴ are N and Z³, Z⁵, Z⁶and Z⁷ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z¹, Z³ and Z⁴ are N and Z², Z⁵, Z⁶ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z³ and Z⁴ areN and Z¹, Z², Z⁵, Z⁶ and Z⁷ are C(R^(x)), wherein each R^(x) whenpresent is H. In some embodiments, Z², Z⁵ and Z⁷ are N and Z¹, Z³, Z⁴and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z³ and Z⁵ are N and Z¹, Z², Z⁴, Z⁶ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z², Z⁵, Z⁶and Z⁷ are N and Z¹, Z³ and Z⁴ are C(R^(x)), wherein each R^(x) whenpresent is H.

In some embodiments, R^(k′) is selected from the group consisting of H,methyl, ethyl, propyl, iso-propyl, cyclopropyl, 2-hydroxyethyl,2-hydroxy-2-methyl-propyl, and N-methyl-pyrrol-3-yl. In someembodiments, M is CH. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N,and Z², Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present isH. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N, Z², Z³, Z⁵ and Z⁶are C(R^(x)), wherein each R^(x) when present is H, and X¹ is—N(R^(k′))—. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N, Z², Z³,Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H, X¹ is—N(R^(k′))—, and X¹′ is —O—. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷are N, Z², Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when presentis H, X¹ is —C(R^(1a))(R^(2a))—, and X¹′ is —O—.

In some embodiments, compounds of Formula (I) or (I-A) are compoundsselected from the group consisting of

wherein

M is CH or N;

X¹ and X¹′ are independently —C(R^(1a))(R^(2a))—, —S—, —S(O)—, —S(O)₂—,—O— or —N(R^(k′))—; each R^(1a) and R^(2a) is independently H,deuterium, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, —C(O)OR^(a′),—C(O)NR^(a′)R^(b′), —NR^(a′)R^(b′), —SR^(a′), —S(O)R^(a′), —S(O)NR^(a′),—S(O)₂R^(a′), —S(O)₂NR^(a′) or —OR^(a′) wherein each hydrogen atom inC₁₋₆alkyl is independently optionally substituted by deuterium, halogen,—OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, NHC(O)C₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)C₁₋₄alkyl, —NHC(O)NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)NHC₁₋₄alkyl, NHC(O)N(C₁₋₄alkyl)₂,—N(C₁₋₄alkyl)C(O)N(C₁₋₄alkyl)₂, —NHC(O)OC₁₋₄alkyl,—N(C₁₋₄alkyl)C(O)OC₁₋₄alkyl, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl,—S(O)₂C₁₋₄alkyl, —S(O)NH(C₁₋₄alkyl), —S(O)₂NH(C₁₋₄alkyl),—S(O)N(C₁₋₄alkyl)₂, —S(O)₂N(C₁₋₄alkyl)₂, C₃₋₆cycloalkyl, or 3- to7-membered heterocycloalkyl;

R^(3a) and R^(3b) are each independently H, fluoro, chloro, bromo,methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or—CF₃;

R^(7a) is H, C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl, whereineach hydrogen atom in C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —OC₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, cycloalkyl, or monocyclicheterocycloalkyl;

each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl in R^(k)′is independently optionally substituted by deuterium, halogen,C₁₋₆alkyl, C₁₋₆haloalkyl or —OR^(a′);

wherein each R^(a′) and R^(b′) is independently H, deuterium, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or heteroaryl;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R^(x)),wherein each R^(x) when present is independently H, deuterium, halogen,C₁₋₄alkyl, —O—C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —NH(phenyl),—NH(heteroaryl), CN, or —CF₃, provided that at least one of Z¹, Z², Z³,Z⁴, Z⁵, Z⁷ or Z is N or NH; and

m′ is 2 or 3;

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z¹, Z⁴ and Z⁷ are N, and Z², Z³, Z⁵ and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z¹and Z³ are N, Z⁷ is NH and Z², Z⁴, Z⁵, and Z⁶ are C(R^(x)), wherein eachR^(x) when present is H. In some embodiments, Z¹, Z³ and Z⁶ are, N Z⁷ isNH and Z², Z⁴ and Z⁵ are C(R^(x)), wherein each R^(x) when present is H.In some embodiments, Z³ is N, Z⁷ is NH and Z¹, Z², Z⁴, Z⁵, and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z³and Z⁶ are N, Z⁷ is NH and Z¹, Z², Z⁴ and Z⁵ are C(R^(x)), wherein eachR^(x) when present is H. In some embodiments, Z², Z⁴ and Z⁷ are N andZ¹, Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. Insome embodiments, Z¹, Z⁵ and Z⁷ are N and Z², Z³, Z⁴ and Z⁶ areC(R^(x)), wherein each R^(x) when present is H. In some embodiments, Z¹,Z², Z⁴ and Z⁷ are N and Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x)when present is H. In some embodiments, Z¹, Z², Z⁵ and Z⁷ are N and Z³,Z⁴ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z³, Z⁵ and Z⁶ are N and Z¹, Z², Z⁴ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z¹, Z⁵, Z⁶and Z⁷ are N and Z², Z³ and Z⁴ are C(R^(x)), wherein each R^(x) whenpresent is H. In some embodiments, Z¹, Z² and Z⁴ are N and Z³, Z⁵, Z⁶and Z⁷ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z¹, Z³ and Z⁴ are N and Z², Z⁵, Z⁶ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z³ and Z⁴ areN and Z¹, Z², Z⁵, Z⁶ and Z⁷ are C(R^(x)), wherein each R^(x) whenpresent is H. In some embodiments, Z², Z⁵ and Z⁷ are N and Z¹, Z³, Z⁴and Z⁶ are C(R^(x)), wherein each R^(x) when present is H. In someembodiments, Z³ and Z⁵ are N and Z¹, Z², Z⁴, Z⁶ and Z⁷ are C(R^(x)),wherein each R^(x) when present is H. In some embodiments, Z², Z⁵, Z⁶and Z⁷ are N and Z¹, Z³ and Z⁴ are C(R^(x)), wherein each R^(x) whenpresent is H.

In some embodiments, R^(k′) is selected from the group consisting of H,methyl, ethyl, propyl, iso-propyl, cyclopropyl, 2-hydroxyethyl,2-hydroxy-2-methyl-propyl, and N-methyl-pyrrol-3-yl. In someembodiments, M is CH. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N,and Z², Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present isH. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N, Z², Z³, Z⁵ and Z⁶are C(R^(x)), wherein each R^(x) when present is H, and X¹ is—N(R^(k′))—. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷ are N, Z², Z³,Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H, X¹ is—N(R^(k′))—, and X¹′ is —O—. In some embodiments, M is CH, Z¹, Z⁴ and Z⁷are N, Z², Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when presentis H, X¹ is —C(R^(1a))(R^(2a)) and X¹′ is —O—.

In other embodiments, the compound of Formula (I) or (I-A) is selectedfrom the group consisting of(13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;2-[(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide;2-[12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide;(13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-7-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;(7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;(5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one;3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one;(5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one;3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one;(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one;(7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one;8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)pyrrolo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)imidazo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-etheno[1,2,4]triazolo[3,4-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)[1,2,4]triazolo[3,4-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one;8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one;8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-16(13H)-one;12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(azenometheno)pyrrolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;(8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;(7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;and9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;or a pharmaceutically acceptable salt thereof.

In other embodiments, the compound of Formula (I) or (I-A) is selectedfrom the group consisting of12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-3,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;14-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;14-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;11-fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;11-fluoro-7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;methyl11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxylate;11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one;11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one;11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one;13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one;13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one;11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one14,14-dioxide;6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][10,1,4,8]benzoxathiadiazacyclotridecin-4(5H)-one;14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;11-fluoro-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one13,13-dioxide;11-fluoro-14-methyl-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one13,13-dioxide;12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e][2,4,10]benzotriazacyclotridecin-8-one;11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzoxatriazacyclotridecin-8(5H)-one;11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e][2,4,7,10]benzotetraazacyclotridecin-8-one;11-fluoro-4,7,14-trimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e][2,4,7,10]benzotetraazacyclotridecin-8-one;11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzothiatriazacyclotridecin-8(5H)-one;11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzothiatriazacyclotridecin-8(5H)-one4,4-dioxide; and12-fluoro-8,15-dimethyl-5,6,7,8,14,15-hexahydro-9H-1,16-ethenopyrazolo[3,4-e][7,2,4,8,11]benzothiatetraazacyclotetradecin-9-one4,4-dioxide; or a pharmaceutically acceptable salt thereof.

In other embodiments, the compound of Formula (I) or (I-A) is selectedfrom the group consisting of11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-methyl(6,6,7,7-²H₄)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;13-(cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7R,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7S,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7R,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-fluoro-7-hydroxy-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-fluoro-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9]benzoxadiazacyclotetradecin-4-one;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one8-oxide;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one8,8-dioxide;(7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8]benzoxadiazacyclotridecin-4(5H)-one;(6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(6R,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;and11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one;or a pharmaceutically acceptable salt thereof.

In other embodiments, the compound of Formula (I) or (I-A) is selectedfrom the group consisting of(13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;2-[(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide;(13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;(7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;(5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one;(5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one;(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one;(7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one;(13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;(7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;(13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7R,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7S,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7R,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8]benzoxadiazacyclotridecin-4(5H)-one;(6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(6R,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;and(7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;or a pharmaceutically acceptable salt thereof.

The following represent illustrative embodiments of compounds of Formula(I) or (I-A):

Ex. Structure Chemical Name 1

(13R)-5,13-dimethyl-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 1-1

5,13-dimethyl-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 2

(13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 2-1

11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-(5H)-one 3

(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 3-1

12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 4

(13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 4-1

12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 5

2-[(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)- yl]acetamide 5-1

2-[12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)- yl]acetamide 6

(13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 6-1

12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 7

(13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 7-1

12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 8

(13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 8-1

11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 9

(13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 9-1

13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 10

(13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 10-1

11-fluoro-13-methyl-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 11

(13R)-12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 11-1

12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 12

12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 13

12-chloro-11-fluoro-7-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one 14

(8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1- f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one 14-1

9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6- ethenoimidazo[5,1- f][1,10,4,7,8]benzodioxatriazacyclotridecin- 17(14H)-one 15

(7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)- one 15-1

8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)- one 16

(5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one 16-1

3-fluoro-5-methyl-14,15-dihydro-5H,10H-9.7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one 17

(5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9.7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin- 12(10H)-one 17-1

3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one 18

(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one 18-1

12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one 19

(7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4- f][1,10,4]benzodioxazacyclotridecin-16(13H)-one 19-1

8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one 20

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzotriazacyclotridecin-4(5H)-one 21

(13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 21-1

12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 22

12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one 23

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 24

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 25

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one 26

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro- 3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)- one 27

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)- one 28

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one 29

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)pyrrolo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one 30

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)imidazo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one 31

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-etheno[1,2,4]triazolo[3,4-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)- one 32

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)[1,2,4]triazolo[3,4-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one 33

8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one 34

8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one 35

8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-16(13H)-one 36

12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(azenometheno)pyrrolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one 37

(8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H- 3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin- 17(14H)-one 37-1

10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6- ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin- 17(14H)-one 38

(7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)- one 38-1

9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)- oneand pharmaceutically acceptable salts thereof.

The following represent illustrative embodiments of compounds of Formula(I) or (I-A):

Ex. Structure Chemical Name 39

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 40

11-fluoro-3,14-dimethyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 41

10-fluoro-8-methyl-15,16-dihydro-8H-3,6- ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin- 17(14H)-one 42

10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6- ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)- one 43

14-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 44

11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 45

11-fluoro-14-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 46

14-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 47

11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 48

11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 49

14-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 50

11-fluoro-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 51

11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 51-1

(13R)-11-fluoro-13-methyl-6,7,13,14- tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 52

12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 53

11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7- carboxamide 54

11-fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 55

11-fluoro-13-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7- carboxamide 56

11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 57

11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7- carboxamide 58

11-fluoro-7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 59

methyl 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13- carboxylate 60

11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13- carboxamide 61

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one 62

11-fluoro-14-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one 63

11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one 64

11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one 65

13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one 66

13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 67

11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one 68

11-fluoro-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 69

11-fluoro-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 14,14-dioxide 70

6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][10,1,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 71

14-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 72

13-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 73

11-fluoro-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)- one 13,13-dioxide74

11-fluoro-14-methyl-6,7-dihydro-5H-1,15- ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)- one 13,13-dioxide75

12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H- 1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one 76

12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H- 1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one 76-1

(14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one 77

11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4- e][2,4,10]benzotriazacyclotridecin-8-one 78

11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[3,4-e][7,2,4,10]benzoxatriazacyclotridecin-8(5H)-one 79

11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4- e][2,4,7,10]benzotetraazacyclotridecin-8-one80

11-fluoro-4,7,14-trimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4- e][2,4,7,10]benzotetraazacyclotridecin-8-one81

11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[3,4-e][7,2,4,10]benzothiatriazacyclotridecin-8(5H)-one 82

11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[3,4-e][7,2,4,10]benzothiatriazacyclotridecin-8(5H)-one 4,4-dioxide 83

12-fluoro-8,15-dimethyl-5,6,7,8,14,15-hexahydro-9H-1,16-ethenopyrazolo[3,4-e][7,2,4,8,11]benzothiatetraazacyclotetradecin-9-one 4,4-dioxide

and pharmaceutically acceptable salts thereof.

The following represent illustrative embodiments of compounds of Formula(I) or (I-A):

Ex. Structure Chemical Name 84

11-chloro-13-methyl-6,7,13,14-tetrahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 85

13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 86

13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 87

11-fluoro-14-methyl(6,6,7,7-²H₄)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 88

11-fluoro-13-phenyl-6,7,13,14-tetrahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 89

13-(cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 90

(7R,14R)-12-fluoro-7-hydroxy-14-methyl- 5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3- g][1,5,9,11]benzoxatriazacyclotetradecin-4- one 91

(7S,14R)-12-fluoro-7-hydroxy-14-methyl- 5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3- g][1,5,9,11]benzoxatriazacyclotetradecin-4- one 92

(7R,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 93

(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 94

(7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 95

(6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 96

12-fluoro-7-hydroxy-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4- one 97

(7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 98

11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 99

12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4- one 100

11-fluoro-13,14-dimethyl-6,7,13,14- tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 101

11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 102

11-fluoro-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8]benzoxadiazacyclotridecin-4(5H)-one 103

12-fluoro-5,6,7,8,14,15-hexahydro-4H-1,16- ethenopyrazolo[4,3-g][1,5,9]benzoxadiazacyclotetradecin-4-one 104

11-fluoro-14-methyl-6,7,13,14-tetrahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H) one 105

11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 106

11-fluoro-14-methyl-6,7,13,14-tetrahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H) one 8-oxide 107

11-fluoro-14-methyl-6,7,13,14-tetrahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)- one 8,8-dioxide 108

(7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro- 1,15-ethenopyrazolo[4,3-f][1,4,8]benzoxadiazacyclotridecin-4(5H)-one 109

(6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 110

(6R,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 111

(7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one 112

11-fluoro-6,7-dihydro-13H-1,15- ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)- one

and pharmaceutically acceptable salts thereof.

Those skilled in the art will recognize that the species listed orillustrated herein are not exhaustive, and that additional specieswithin the scope of these defined terms may also be selected.

Pharmaceutical Compositions

For treatment purposes, pharmaceutical compositions comprising thecompounds described herein may further comprise one or morepharmaceutically-acceptable excipients. A pharmaceutically-acceptableexcipient is a substance that is non-toxic and otherwise biologicallysuitable for administration to a subject. Such excipients facilitateadministration of the compounds described herein and are compatible withthe active ingredient. Examples of pharmaceutically-acceptableexcipients include stabilizers, lubricants, surfactants, diluents,anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, ortaste-modifying agents. In preferred embodiments, pharmaceuticalcompositions according to the invention are sterile compositions.Pharmaceutical compositions may be prepared using compounding techniquesknown or that become available to those skilled in the art.

Sterile compositions are also contemplated by the invention, includingcompositions that are in accord with national and local regulationsgoverning such compositions.

The pharmaceutical compositions and compounds described herein may beformulated as solutions, emulsions, suspensions, or dispersions insuitable pharmaceutical solvents or carriers, or as pills, tablets,lozenges, suppositories, sachets, dragees, granules, powders, powdersfor reconstitution, or capsules along with solid carriers according toconventional methods known in the art for preparation of various dosageforms. Pharmaceutical compositions of the invention may be administeredby a suitable route of delivery, such as oral, parenteral, rectal,nasal, topical, or ocular routes, or by inhalation. Preferably, thecompositions are formulated for intravenous or oral administration.

For oral administration, the compounds the invention may be provided ina solid form, such as a tablet or capsule, or as a solution, emulsion,or suspension. To prepare the oral compositions, the compounds of theinvention may be formulated to yield a dosage of, e.g., from about 0.1mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mgdaily, or about 250 mg to 1 g daily. Oral tablets may include the activeingredient(s) mixed with compatible pharmaceutically acceptableexcipients such as diluents, disintegrating agents, binding agents,lubricating agents, sweetening agents, flavoring agents, coloring agentsand preservative agents. Suitable inert fillers include sodium andcalcium carbonate, sodium and calcium phosphate, lactose, starch, sugar,glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, andthe like. Exemplary liquid oral excipients include ethanol, glycerol,water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starchglycolate, microcrystalline cellulose, and alginic acid are exemplarydisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, may be magnesium stearate, stearicacid, or talc. If desired, the tablets may be coated with a materialsuch as glyceryl monostearate or glyceryl distearate to delay absorptionin the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil, such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups, or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

For parenteral use, including intravenous, intramuscular,intraperitoneal, intranasal, or subcutaneous routes, the agents of theinvention may be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms may be presented in unit-dose formsuch as ampoules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Illustrative infusion doses range from about 1 to 1000μg/kg/minute of agent admixed with a pharmaceutical carrier over aperiod ranging from several minutes to several days.

For nasal, inhaled, or oral administration, the inventive pharmaceuticalcompositions may be administered using, for example, a spray formulationalso containing a suitable carrier. The inventive compositions may beformulated for rectal administration as a suppository.

For topical applications, the compounds of the present invention arepreferably formulated as creams or ointments or a similar vehiclesuitable for topical administration. For topical administration, theinventive compounds may be mixed with a pharmaceutical carrier at aconcentration of about 0.1% to about 10% of drug to vehicle. Anothermode of administering the agents of the invention may utilize a patchformulation to effect transdermal delivery.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying systemic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human.

Exemplary diseases include cancer, pain, neurological diseases,autoimmune diseases, and inflammation. Cancer includes, for example,lung cancer, colon cancer, breast cancer, prostate cancer,hepatocellular carcinoma, renal cell carcinoma, gastric andesophago-gastric cancers, glioblastoma, head and neck cancers,inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.Pain includes, for example, pain from any source or etiology, includingcancer pain, pain from chemotherapeutic treatment, nerve pain, pain frominjury, or other sources. Autoimmune diseases include, for example,rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.Exemplary neurological diseases include Alzheimer's Disease, Parkinson'sDisease, Amyotrophic lateral sclerosis, and Huntington's disease.Exemplary inflammatory diseases include atherosclerosis, allergy, andinflammation from infection or injury.

In one aspect, the compounds and pharmaceutical compositions of theinvention specifically target tyrosine receptor kinases, in particularMET, ALK, AXL, TRKs, and JAKs. Thus, these compounds and pharmaceuticalcompositions can be used to prevent, reverse, slow, or inhibit theactivity of one or more of these kinases. In preferred embodiments,methods of treatment target cancer. In other embodiments, methods arefor treating lung cancer or non-small cell lung cancer.

In the inhibitory methods of the invention, an “effective amount” meansan amount sufficient to inhibit the target protein. Measuring suchtarget modulation may be performed by routine analytical methods such asthose described below. Such modulation is useful in a variety ofsettings, including in vitro assays. In such methods, the cell ispreferably a cancer cell with abnormal signaling due to upregulation ofMET, ALK, AXL, TRKs, and/or JAKs.

In treatment methods according to the invention, an “effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic benefit in subjects needing such treatment. Effectiveamounts or doses of the compounds of the invention may be ascertained byroutine methods, such as modeling, dose escalation, or clinical trials,taking into account routine factors, e.g., the mode or route ofadministration or drug delivery, the pharmacokinetics of the agent, theseverity and course of the infection, the subject's health status,condition, and weight, and the judgment of the treating physician. Anexemplary dose is in the range of about from about 0.1 mg to 1 g daily,or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250mg to 1 g daily. The total dosage may be given in single or divideddosage units (e.g., BID, TID, QID).

Once improvement of the patient's disease has occurred, the dose may beadjusted for preventative or maintenance treatment. For example, thedosage or the frequency of administration, or both, may be reduced as afunction of the symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms. Patients may also require chronic treatment on along-term basis.

Drug Combinations

The inventive compounds described herein may be used in pharmaceuticalcompositions or methods in combination with one or more additionalactive ingredients in the treatment of the diseases and disordersdescribed herein. Further additional active ingredients include othertherapeutics or agents that mitigate adverse effects of therapies forthe intended disease targets. Such combinations may serve to increaseefficacy, ameliorate other disease symptoms, decrease one or more sideeffects, or decrease the required dose of an inventive compound. Theadditional active ingredients may be administered in a separatepharmaceutical composition from a compound of the present invention ormay be included with a compound of the present invention in a singlepharmaceutical composition. The additional active ingredients may beadministered simultaneously with, prior to, or after administration of acompound of the present invention.

Combination agents include additional active ingredients are those thatare known or discovered to be effective in treating the diseases anddisorders described herein, including those active against anothertarget associated with the disease. For example, compositions andformulations of the invention, as well as methods of treatment, canfurther comprise other drugs or pharmaceuticals, e.g., other activeagents useful for treating or palliative for the target diseases orrelated symptoms or conditions. For cancer indications, additional suchagents include, but are not limited to, kinase inhibitors, such as EGFRinhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g.,vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapyagents such as alkylating agents, antimetabolites, anti-tumorantibiotics, topoisomerase inhibitors, platinum drugs, mitoticinhibitors, antibodies, hormone therapies, or corticosteroids. For painindications, suitable combination agents include anti-inflammatoriessuch as NSAIDs. The pharmaceutical compositions of the invention mayadditional comprise one or more of such active agents, and methods oftreatment may additionally comprise administering an effective amount ofone or more of such active agents.

Chemical Synthesis

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used. Unless otherwise specified, thevariables are as defined above in reference to Formula (I). Isotopicallylabeled compounds as described herein are prepared according to themethods described below, using suitably labeled starting materials. Suchmaterials are generally available from commercial suppliers ofradiolabeled chemical reagents.

General Method A:

It will be appreciated that compounds of the formula A or A-1 can bemade according to General Method A using appropriately functionalizedstarting materials and intermediates.

Step 1. To a solution of an appropriately functionalized compound A-1(˜1.00 eq.), where R^(A) and R^(B) are groups compatible with thereaction conditions described herein and Nu is a nucleophilic group suchas an anion or a group capable of forming a nucleophile, such as ahalide, in a reagent capable of promoting the compoling of A-1 and A-2,such as an acid (e.g. TfOH (0.6 M)) or an alkyl halide (e.g. n-BuLi) canbe added A-2, where R^(C) is a group compatible with the reactionconditions described herein and X² is, for example, a leaving group(˜1.00 eq.) at an appropriate temperature (e.g. 0° C.). The mixture canbe stirred at an appropriate temperature (e.g. 60° C.) until thereaction is completed. The reaction can then be returned to ambienttemperature, and the reaction mixture can be quenched, neutralized,washed, extracted, dried and/or concentrated under vacuum as needed togive A-3.

Step 2. A mixture of A-3, where R^(A), R^(B) and R^(C) are groupscompatible with the reaction conditions described herein (in someexemplary embodiments described herein, A-3 can be a commerciallyavailable aldehyde or ketone, or A-3 can be prepared from step 1, ˜1.00eq.) and commercially available amine A-4, where R^(C) is a groupcompatible with the reaction conditions described herein, (˜1.50 eq.) inan appropriate solvent (e.g. methanol (0.5 M)) can be stirred at anappropriate temperature (e.g. ambient temperature) for an appropriateamount of time or until the imine formation is complete by TLC or LC-MS.To the reaction solution can be added a reducing agent (e.g. NaBH₄(˜2.00 eq.)) portion-wise. The mixture can be stirred at an appropriatetemperature (e.g. ambient temperature) until TLC or LC-MS shows thereduction to be complete. The reaction can be quenched, washed,extracted, dried and or concentrated under vacuum as needed to provideA-5.

Step 3. A mixture of a prepared or commercial available A-5, whereR^(A), R^(B) and R^(C) are groups compatible with the reactionconditions described herein (˜1 eq.), commercially available ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, ˜1 eq.) and anappropriate base (e.g. diisopropylethylamine (˜5 eq.)) in an appropriatesolvent (e.g. butanol (0.4 M)) can be stirred at an appropriatetemperature (e.g. 110° C.) for a set length of time or until thereaction is shown to be complete. The reaction can be returned toambient temperature and diluted with water as needed. The mixture can beextracted, washed, dried, concentrated under reduced pressure and/orpurified by chromatographic methods as needed to provide A.

In some exemplary embodiments, General Method A can be carried out asfollows:

Step 1. To a solution of A-1 (1.00 eq.) in TfOH (0.6 M) can be added A-2(1.00 eq.) at 0° C. The mixture can be stirred at 60° C. for 4 hours oruntil the reaction was completed. After cooling to ambient temperature,the reaction mixture can be poured into ice-water (w/w=1/1), neutrolizedwith NaHCO₃ to pH˜9, and extracted with EtOAc three times as needed. Thecombined organic layers can be washed with brine, dried over anhydrousNa₂SO₄ as needed, and concentrated to give A-3.

Step 2. A mixture of A-3 (commercially available aldehyde or ketone, orprepared from step 1, 1.00 eq.) and commercially available amine A-4(1.50 eq.) in methanol (0.5 M) can be stirred at ambient temperature for2 hour or until the imine formation is shown to be complete by TLC orLC-MS. To the reaction solution can be added NaBH₄ (2.00 eq.)portion-wise. The mixture can be stirred at ambient temperature untilTLC or LC-MS shows the reduction to be complete. The reaction can bequenched with water and extracted three times with dichloromethane asneeded. The combined organic phase can be washed with brine, dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to afford A-5.

Step 3. The prepared or commercial available A-5 (1 eq.), ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, 1 eq.) anddiisopropylethylamine (5 eq.) in butanol (0.4 M) can be heated at 110°C. for 30 minutes or until the reaction is shown to be complete. Thereaction can be cooled and diluted with water. The mixture can beextracted with dichloromethane four times (as needed) and the combinedextracts can be dried over anhydrous sodium sulfate. After filtration,the mixture can be concentrated under reduced pressure and the residuecan be purified via flash chromatography to provide A.

Alternate General Method A:

Coupling Step 1. The mixture of an appropriately functionalized AA-1(˜1.00 eq.), an appropriately functionalized vinyl coupling reagent(˜1.00-1.50 eq.) and a palladium catalyst (˜0.05 eq.) under appropriatereaction conditions can be heated to an appropriate temperature (e.g.˜90° C.) for an appropriate amount of time under inert atmosphere untilTLC indicates that the starting material to be completely consumed. Thereaction mixture can be poured into H₂O as needed. The mixture can beextracted and the organic phase washed, dried, concentrated, andpurified via silica gel column chromatography as needed to afford AA-2.

Coupling Step 2. The mixture of a compound of the type AA-2 (˜1.00 eq.),ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, ˜1.00 eq.)and a palladium catalyst under appropriate reaction conditions can beheated to an appropriate temperature (e.g. 120° C.) for an appropriatelength of time under inert atmosphere until TLC indicates the startingmaterial to be completely consumed. The reaction mixture can be pouredinto H₂O as needed. The mixture can be extracted and the organic phasecan be washed, dried, concentrated, and purified via silica gel columnchromatography as needed to afford AA-3.

Step 3. To a mixture of AA-3 (˜1.00 eq.) and4-methylbenzenesulfonohydrazide (in molar excess) in a suitable solventcan be added an appropriate base (in molar excess) at an appropriatetemperature under inert atmosphere. The mixture can be heated to anappropriate temperature (e.g. 65° C.) and stirred for an appropriateamount of time until TLC indicates the reaction to be complete. Themixture can be cooled and concentrated under reduced pressure as needed.The concentrated reaction mixture can be diluted with water as needed,and extracted. The combined organic phase can be washed, dried,filtered, concentrated in vacuum, and purified to afford AA-4.

General Method B:

Step 1. A solution of aldehyde B-1 (˜1.0 eq) where R^(A) and R^(B) aregroups compatible with the reaction conditions described herein, B-2(˜1.0 eq) where X¹ is a leaving group and PG is a protecting group, ansuitable base (in molar excess) and a catalyst in an suitable solventcan be heated and stirred for an appropriate amount of time until thereaction is complete. Additional B-2 can be added and further heatingapplied as needed. The mixture can be cooled to ambient temperature anddiluted with water as needed. The mixture can be extracted, and thecombined extracts can be washed, dried, and concentrated under reducedpressure as needed. The crude reaction product can be purified via flashchromatography to provide B-3.

Step 2. Aldehyde B-3 (˜1.0 eq) and an appropriately functionalized amine(˜2.0-4.0 eq) where R^(C) is a group compatible with the reactionconditions described herein in an appropriate solvent can be heated andstirred for an appropriate amount of time. The mixture can be cooled toambient temperature and a suitable reducing agent (˜1.0 eq) can beadded. The mixture can be stirred for an appropriate amount of time thenquenched by addition of water as needed. The mixture can be extractedwith an appropriate organic solvent, and the combined extracts can bewashed, dried and concentrated under reduced pressure as needed. Thecrude reaction product can be purified via flash chromatography asneeded to provide B-4.

Step 3. Compound B-4 (˜1.0 eq), ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, ˜1.0 eq) and asuitable base (in molar excess) in a suitable solvent can be heated foran appropriate amount of time. The reaction can be cooled and dilutedwith water as needed. The mixture can be extracted with a suitableorganic solvent, and the combined extracts can be dried and concentratedunder reduced pressure as needed. The crude reaction product can bepurified via flash chromatography to provide B1.

In some exemplary embodiments, General Method B can be carried out asfollows:

Step 1. A solution of aldehyde B-1 (˜1.0 eq) where R^(A) and R^(B) aregroups compatible with the reaction conditions described herein, B-2(˜1.0 eq) where X¹ is a leaving group and PG is a protecting group,potassium carbonate (in molar excess) and potassium iodide (catalyticamount) in DMF can be heated to 60° C. and stirred for ˜15 hours.Additional chloride B-2 can be added and further heating at 80° C. canbe applied as needed until the reaction is shown to be complete. Themixture can be cooled to ambient temperature and diluted by addition ofwater (250 mL) as needed. The mixture can be extracted with ethylacetate (3×300 mL) and the combined extracts can be washed with water(200 mL) and brine (100 mL), can be dried with sodium sulfate, andconcentrated under reduced pressure as needed. The crude reactionproduct can be purified via flash chromatography to provide B-3.

Step 2. Aldehyde B-3 (˜1.0 eq) and methylamine (˜2.5 eq) in methanol canbe heated to 60° C. and stirred for ˜1 hour. The mixture can be cooledto ambient temperature and sodium borohydride (˜1.0 eq) can be added.The mixture can be stirred for ˜30 minutes then quenched by addition ofwater (200 mL) as needed. The mixture can be extracted withdichloromethane and the combined extracts can be washed with brine (50mL), can be dried with sodium sulfate and concentrated under reducedpressure as needed. The crude reaction product can be purified via flashchromatography to provide B-4.

Step 3. Amine B-4 (˜1.0 eq), ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, ˜1.0 eq) andhünig's base (in molar excess) in butanol can be heated at 110° C. for˜25 minutes. The reaction can be cooled and diluted with water (250 mL).The mixture can be extracted with dichloromethane and the combinedextracts can be dried with sodium sulfate as needed. The mixture can beconcentrated under reduced pressure as needed. The crude reactionproduct can be purified via flash chromatography to provide B.

General Method C

Step 1. To a solution of C-1 (˜1.0 eq.) where R^(A), R^(B), R^(C), R^(D)and R^(E) are groups compatible with the reaction conditions describedherein, X¹AlkNHPG (˜1.5-2.0 eq.) where X¹ is a leaving group, Alk is anappropriately functionalized alkyl group and PG is a protecting group ina suitable solvent can be added a suitable base (˜3.0 eq.). The mixturecan be heated to an appropriate temperature for an appropriate amount oftime under inert atmosphere until complete conversion of the startingmaterial to the product is shown by LC-MS. The mixture can be cooled toambient temperature, diluted with water and extracted with an suitableorganic solvent as needed. The combined organic extracts can be washedwith water and brine, dried over Na₂SO₄, and concentrated as needed. Theresulting residue can be purified via silica gel column chromatographyas needed to afford C-2.

Step 2. To a solution of C-2 (1 eq.) where R^(A), R^(C), R^(D) and R^(E)are groups compatible with the reaction conditions described herein, Alkis an appropriately functionalized alkyl group and PG is a protectinggroup in a suitable solvent can be added a suitable base (in molarexcess). The solution can be heated at to an appropriate temperature foran appropriate amount of time. The reaction can be neutralized with asuitable acid to pH<5, and the reaction mixture can be extracted with asuitable organic solvent. The combined organics can be washed and can bedried as needed. The crude reaction product mixture can be filtered,concentrated under reduced pressure, and dried under high vacuum asneeded to provide C-3.

Step 3. To a solution of C-3 (˜1.0 eq.) in a suitable organic solventcan be added a suitable acid (˜4 eq.) at an appropriate temperature(e.g. 0° C.). The reaction mixture can be stirred at an appropriatetemperature for an appropriate amount of time until the reaction isshown to be complete by LC-MS. The crude product can be filtered,washed, and can be dried under high vacuum to provide a C-4.

Step 4a. To a solution of C-4 (˜1.0 eq.) in a suitable solvent can beadded a suitable base (in molar excess). The solution can be cooled inan ice water bath and a suitable coupling agent (˜1.5 eq.) can be addedto produce an activated ester. The solution can be warmed to ambienttemperature slowly and stirred until the starting material is shown toconvert to the desired product by LC-MS. The mixture can be diluted withwater and extracted with a suitable organic solvent as needed. Thecombined organic extracts can be washed, dried, and concentrated underreduced pressure as needed. The resulting residue can be purified by asilica gel column chromatography to afford C.

In some exemplary embodiments, General Method C can be carried out asfollows:

Step 1. To a solution of C-1 (˜1.0 eq.), where R^(A), R^(B), R^(C),R^(D) and R^(E) are groups compatible with the reaction conditionsdescribed herein, X¹AlkNHPG (˜1.5-2.0 eq.) where X¹ is a leaving group,Alk is an appropriately functionalized alkyl group and PG is aprotecting group in DMF (0.5 M) can be added K₂CO₃ (˜3.0 eq.). Themixture can be heated at 80° C. for ˜2 hours or until completeconversion of the starting material to the product can be shown byLC-MS. The mixture can be cooled to ambient temperature, diluted withwater as needed and extracted three times with EtOAc as needed. Thecombined organic layers can be then washed with water and brine, can bedried over Na₂SO₄, and concentrated as needed. The resulting residue canbe purified via silica gel column chromatography eluting withEtOAc/Hexane (5-100%, 10CV) to afford C-2.

Step 2. To a solution of C-2 (˜1 eq.) in methanol/THF/H2O (3:1:1, 0.2M)can be added LiOH.H2O (˜5.0 eq.). The solution can be heated at 70° C.for ˜2 hours The reaction can be neutralized at ˜0° C. with aq. HCl (2M)to pH<5, and extracted four times with CH₂Cl₂ as needed. The combinedorganic extracts can be washed with brine, and can be dried over Na₂SO₄as needed. The crude product mixture can be filtered, concentrated underreduced pressure, and dried under high vacuum as needed to provide C-3.

Step 3. To a solution of C-3 (˜1.0 eq.) in CH₂Cl₂ (0.25M) can be addedHCl in dioxane (4 M, ˜4 eq.) at ˜0° C. The reaction can be stirred andallowed to warm from 0° C. to room temperature for about 27 hours oruntil the reaction can be shown to be complete by LC-MS. The resultingreaction mixture can be filtered, washed with CH₂Cl₂, and dried underhigh vacuum as needed to provide C-4.

Step 4a. Cyclization with HATU. To a solution of C-4 (˜1.0 eq.) in ˜10mL of DMF (˜0.005M) can be added DIPEA (˜5.0 eq.). The solution can becooled in an ice water bath and HATU (˜1.5 eq.) can be added. Thesolution can be allowed to warm to ambient temperature and stirred untilsuch time as complete conversion of the starting material to the desiredproduct can be shown by LC-MS. The mixture can be diluted with water andextracted three times with EtOAc as needed. The combined organicextracts can be washed with water and brine, dried over Na₂SO₄, andconcentrated under reduced pressure as needed. The resulting residue canbe purified via silica gel column chromatography (0-5% MeOH/DCM) toafford C.

Step 4b. Cyclization with FDPP. To a solution of DIPEA (˜5 eq.) inDMF/CH₂Cl₂ (3:1, ˜0.005M) can be added C-4 (˜1.00 eq.). After C-4dissolves completely, pentafluorophenyl diphenylphosphinate (FDPP, ˜1.05eq.) can be added. The coupling can be allowed to stir for 30 minutes oruntil such time as the reaction is shown to be complete by LC-MS. Thereaction solution can be diluted with CH₂Cl₂, washed three times withwater, aqueous Na₂CO₃ (2 M) and brine, can be dried over Na₂SO₄ asneeded. After filtration and concentration under reduced pressure, theresidue can be purified via silica gel column chromatography elutingwith MeOH/CH₂Cl₂ (0-5%) to provide C.

EXAMPLES

The following examples are offered to illustrate but not to limit theinvention. One of skill in the art will recognize that the followingsynthetic reactions and schemes may be modified by choice of suitablestarting materials and reagents in order to access other compounds ofFormula (I) or (I-A). Bicyclic heteroaromatic groups with suitablefunctionality for use in the synthetic methods are commerciallyavailable.

ABBREVIATIONS

The examples described herein use materials, including but not limitedto, those described by the following abbreviations known to thoseskilled in the art:

Abbreviation Name TLC thin layer chromatography PLC preparative liquidchromatography HPLC high performance liquid chromatography LCMS, LC-MSliquid chromatography mass spectrometry LRESIMS low resolutionelectrospray ionization mass spectrometry ELISA enzyme-linked immunoassay DCM dichloromethane DMSO dimethylsufoxide DIPEA, DIEAdi-isopropylethyl amine CDI 1,1′-Carbonyldiimidazole THF tetrahydrofuranXantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene TBSCltert-butyldimethylsilyl chloride DMF N,N-dimethylformamide HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium3-oxid hexafluorophosphate ACN acetonitrile EtOAc ethyl acetate DTADdi-tert-butyl azodicarboxylate FDFF pentafluorophenyldiphenylphosphinate FBS fetal bovine serum BSA bovine serum albumin PBSphosphate buffered silane DMEM Dulbecco's modified eagle medium EDTAEthylenediaminetetraacetic acid RIPA radioimmunoprecipitation assayHEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)

Example A6

Step 1. To a solution of 5-fluoro-2-hydroxybenzaldehyde (500.00 mg, 3.57mmol, 1.00 eq.) in MeOH (20.00 mL) was added 1-methylpyrrolidin-3-amine(357.43 mg, 3.57 mmol, 1.00 eq.) in one portion at 16° C. under N₂. Themixture was stirred at 16° C. for 10 hours under N₂. Then NaBH₄ (270.00mg, 7.14 mmol, 2.00 eq.) was added and the mixture was stirred at 16° C.for 6 hours under N₂. TLC (DCM:MeOH=15:1) showed the reaction wascompleted. The reaction mixture was concentrated under reduced pressureto remove MeOH. The residue was diluted with water (50 mL) and extractedwith DCM (20 mL×3). The combined organic layers were washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give A6-5 (350.00 mg, 1.56 mmol, 43.71% yield) as yellowsolid. ¹HNMR (300 MHz, DMSO-d₆) δ 6.94 (dd, J=2.7, 9.3 Hz, 1H), 6.86(dt, J=3.0, 8.6 Hz, 1H), 6.67 (dd, J=4.7, 8.7 Hz, 1H), 3.71 (s, 2H),3.24-3.09 (m, 1H), 2.58 (dd, J=7.1, 8.8 Hz, 1H), 2.48-2.32 (m, 2H),2.30-2.17 (m, 4H), 2.05-1.82 (m, 1H), 1.60-1.43 (m, 1H).

Step 2. To a solution of A6-5 (300.00 mg, 1.34 mmol, 1.00 eq.) and ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (302.34 mg, 1.34 mmol,1.00 eq.) in n-BuOH (40.00 mL) was added DIPEA (1.04 g, 8.04 mmol, 6.00eq.) at 16° C. under N₂. The mixture was stirred at 120° C. for 2 hours.TLC (PE:EtOAc=1:1) showed the reaction was completed. The mixture waspour into water (50 mL) and extracted by DCM (50 mL×3). The mixture waspurified by Pre-PLC to give A6 formic acid salt (290.00 mg, 701.43 umol,52.35% yield) as a white solid.

Example A8

To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate(1.25 g, 5.54 mmol) and (R)-2-(1-aminoethyl)-4-fluorophenol HCl salt(purchased from NetChem, Inc.) in EtOH (15.83 mL) was added Hunig's base(3.58 g, 27.70 mmol) and heated to 70° C. for 1.5 hour. The reaction wasrotovaped to dryness, suspended in water, and extracted with DCM (5×50mL). The combined extracts were dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (40 g), 0-5%methanol in dichloromethane) provided A8 (1.89 g, 5.49 mmol, 99% yield).

Example A9

Step 1. To a solution of 4-fluorophenol (2.00 g, 17.84 mmol, 1.00 eq.)in TfOH (30.00 mL) was added propanoyl chloride (1.65 g, 17.84 mmol,1.00 eq.) at 0° C. The mixture was stirred at 60° C. for 4 hours TLCshowed the reaction was completed. The mixture was cooled to 25° C.,poured into ice-water (w/w=1/1) (120 mL), neutrolized with NaHCO₃ tomake pH˜9, and extracted with EtOAc (120 mL×3). The combined organiclayers were washed by brine (50 mL), dried with anhydrous Na₂SO₄, andconcentrated to give A9-3 (1.80 g, 10.70 mmol, 59.98% yield) as acolorless oil. ¹HNMR (400 MHz, CDCl₃) δ 12.09 (s, 1H), 7.45 (dd, J=3.0,9.0 Hz, 1H), 7.26-7.20 (m, 1H), 6.97 (dd, J=4.5, 9.0 Hz, 1H), 3.02 (q,J=7.3 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).

Step 2. Ammonia gas was bubbled into MeOH (20 mL) at −78° C. for 10minutes. A9-3 (1.00 g, 5.95 mmol, 1.00 eq.) was added to the solutionand stirred at 25° C. for 1 hr. To the reaction mixture was addedTi(i-PrO)₄ (1.63 g, 7.14 mmol, 1.20 eq.), and the mixture was stirredfor another 1 hr. Then NaBH₄ (449.93 mg, 11.89 mmol, 2.00 eq.) wasadded. The mixture was stirred at 25° C. for 12 hours TLC showed thestarting material was consumed completely. The residue was poured intowater (50 mL) and stirred for 30 mins. The mixture was filtered and thefiltrate was adjusted with HCl (1 M) to pH˜1 and extracted with EtOAc(50 mL×2). Sodium bicarbonate was added to the aqueous phase to adjustpH˜9 and extracted with DCM (50 mL×2). The combined organic layers werewashed with saturated brine (50 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum to afford A9-5 (310.00 mg, 1.83mmol, 30.79% yield) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 6.86(dt, J=3.0, 8.4 Hz, 1H), 6.79-6.74 (m, 1H), 6.67 (dd, J=2.9, 8.9 Hz,1H), 3.98 (t, J=7.0 Hz, 1H), 1.92-1.81 (m, 1H), 1.80-1.68 (m, 1H), 0.95(t, J=7.4 Hz, 3H).

Step 3. A9-5 was coupled with ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate in the presence of DIPEAin n-BuOH to provide A9 as described in General Method A.

Example A13-5 Preparation of2-(1-amino-2-cyclopropylethyl)-4-fluorophenol

Step 1. To a mixture of 2-cyclopropylacetic acid (4.47 g, 44.60 mmol,1.00 eq.) in DCM (150.00 mL) was added CDI (7.96 g, 49.10 mmol, 1.10eq.) in one portion at 25° C. under N₂. The mixture was stirred at 25°C. for 1 hr. Then N-methoxymethanamine hydrochloride (4.79 g, 49.06mmol, 1.10 eq.) was added. The mixture was stirred at 25° C. for another12 hours. The reaction was quenched with 1N aqueous hydrochloric acid(50 mL), and separated into layers. The aqueous layer was extracted withDCM (30 mL×2). The combined organic layer was washed with 50% saturatedaqueous sodium carbonate (50 mL) and saturated brine (30 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to afford2-cyclopropyl-N-methoxy-N-methylacetamide (6.00 g, 41.91 mmol, 93.96%yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 3.65 (s, 1H), 3.18 (s, 1H),2.33 (d, J=6.8 Hz, 2H), 1.13-1.02 (m, 1H), 0.57-0.49 (m, 2H), 0.19-0.11(m, 2H).

Step 2. To a mixture of 2-cyclopropyl-N-methoxy-N-methylacetamide (6.00g, 29.27 mmol, 1.00 eq.) in THF (100.00 mL) was added n-BuLi (2.5 M,12.88 mL, 1.10 eq.) dropwise at −78° C. under N₂. The mixture wasstirred at −78° C. for 10 min. And then the mixture was treated with2-bromo-4-fluoro-1-methoxybenzene (4.19 g, 29.27 mmol, 1.00 eq.) in THF(20 mL) over a period of 20 min. After stirring at −78° C. for 1 hr, themixture was allowed to warm to 25° C. and stirred for one more hour. TLCshowed the reaction was completed. The mixture was poured into 10%aqueous HCl solution (100 mL) and stirred for 10 min. The aqueous phasewas extracted with ethyl acetate (300 mL×3). The combined organic phasewas washed with brine (200 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (Petroleum ether/Ethyl acetate=50/1, 10/1) to afford2-cyclopropyl-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (2.4 g, 39.38%yield) as a colourless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (dd, J=3.3,8.8 Hz, 1H), 7.15 (ddd, J=3.3, 7.5, 9.0 Hz, 1H), 6.91 (dd, J=4.0, 9.0Hz, 1H), 3.91-3.85 (m, 3H), 2.89 (d, J=6.8 Hz, 2H), 1.18-1.05 (m, 1H),0.61-0.50 (m, 2H), 0.20-0.09 (m, 2H).

Step 3. To a solution of2-cyclopropyl-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (500.00 mg, 2.40mmol, 1.00 eq.) in DCM (10.00 mL) was added BCl₃ (1 M, 3.00 mL, 1.25eq.) in drop-wise at −78° C. under N₂. The mixture was stirred at −78°C. for 2 hr. TLC showed the reaction was completed. The mixture waswarmed to 25° C. and poured into ice-water (w/w=1/1) (10 mL) and stirredfor 10 min. The aqueous phase was extracted with ethyl acetate (30mL×3). The combined organic phase was washed with saturated brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum toafford 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (430.00 mg,2.21 mmol, 92.3% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 12.12 (s,1H), 7.40 (dd, J=3.0, 8.8 Hz, 1H), 7.24 (ddd, J=3.0, 7.8, 9.0 Hz, 1H),6.98 (dd, J=4.5, 9.3 Hz, 1H), 2.88 (d, J=6.8 Hz, 2H), 1.23-1.11 (m, 1H),0.70-0.63 (m, 2H), 0.25 (q, J=5.0 Hz, 2H).

Step 4. To a solution of2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (400.00 mg, 1.92mmol, 1.00 eq.) in MeOH (20.00 mL) was added NH₂OH.HCl (160.18 mg, 2.31mmol, 1.20 eq.) and AcONa (189.09 mg, 2.31 mmol, 1.20 eq.) at 25° C.under N₂ for 12 hours. TLC (Petroleum ether/Ethyl acetate=3:1) showedthe starting material was consumed completely. The reaction was quenchedby water and then extracted with DCM (30 mL×3). The combined organicphase was washed with brine (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the pure product2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one oxime (400.00 mg,1.79 mmol, 93.32% yield) as a white solid. The solid was used for thenext step without further purification.

Step 5. To a solution of2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one oxime (260.00 mg,1.16 mmol, 1.00 eq.) in MeOH/HCl (10.00 mL, 4N) was added Pd—C(10%, 100mg) under N₂. The suspension was degassed under vacuum and purged withH₂ several times. The mixture was stirred under H₂ (50 psi) at 50° C.for 12 hours. LC-MS showed the starting material was consumedcompletely. The reaction mixture was filtered and the filterate wasconcentrated to give 2-(1-amino-2-cyclopropylethyl)-4-fluorophenol(200.00 mg, 955.75 umol, 82.39% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.44-9.82 (m, 1H), 8.52 (br. s., 2H), 7.36 (dd, J=2.8,9.5 Hz, 1H), 7.07-6.93 (m, 2H), 4.49 (d, J=5.5 Hz, 1H), 1.82-1.72 (m,2H), 0.67-0.55 (m, 1H), 0.43-0.28 (m, 2H), 0.12-0.06 (m, 1H),(−0.03)-(−0.09) (m, 1H).

Example A14-5 Preparation of 2-(amino(phenyl)methyl)-4-fluorophenol

Step 1. To a solution of A14-3 (2.00 g, 9.25 mmol, 1.00 eq.) and AcOK(1.10 g, 11.20 mmol, 1.20 eq.) in ethanol (30.00 mL) was added NH₂OH.HCl(642.80 mg, 9.25 mmol, 1.00 eq.) in one portion at 25° C. under N₂. Themixture was stirred at 25° C. for 30 mins, then heated to 90° C. andstirred for 5 hours The TLC showed the reaction was completed. Themixture was concentrated and water (50 mL) was added. The mixture wasextracted with ethyl acetate (50 mL×3). The combined organic phase waswashed by brine (50 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated to give (5-fluoro-2-hydroxyphenyl)(phenyl)methanone oxime(1.50 g, 6.49 mmol, 70.13% yield) as a yellow solid. ¹HNMR (400 MHz,CDCl₃) δ 7.50-7.37 (m, 5H), 7.19-7.07 (m, 2H), 6.71 (dd, J=2.9, 8.9 Hz,1H).

Step 2. To a mixture of (5-fluoro-2-hydroxyphenyl)(phenyl)methanoneoxime (900.00 mg, 4.18 mmol, 1.00 eq.) and Zn powder (1.09 g, 16.73mmol, ˜4 eq.) in THF (10.00 mL) was added NH₄Cl (2.24 g, 41.82 mmol,10.00 eq.) in one portion at 25° C. under N₂. The mixture was stirred at25° C. for 30 mins, then heated to 60° C. and stirred for 15 hours. Themixture was concentrated and water (100 mL) was added followed byextraction with ethyl acetate (50 mL×3). The combined organic layerswere washed by brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to give A14-5 (630.00 mg, 2.90 mmol, 69.38% yield) as ayellow solid. ¹HNMR (400 MHz, CDCl₃) δ 7.42 (d, J=7.5 Hz, 2H), 7.33 (t,J=7.5 Hz, 2H), 7.27-7.20 (m, 1H), 6.93-6.80 (m, 2H), 6.70 (dd, J=4.9,8.7 Hz, 1H), 5.28 (s, 1H).

Example A17

Step 1. To a solution of ethyl54(2-bromo-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(prepared according to General Method A) (300.00 mg, 0.736 mmol, 1.00eq.), 2-methylpropane-2-thiol (166.10 mg, 1.84 mmol, 2.50 eq.),Pd₂(dba)₃ (84.72 mg, 0.147 mmol, 0.20 eq.) in dioxane (8.00 mL) wasadded XantPhos (127.87 mg, 0.221 mmol, 0.30 eq.) and K₂CO₃ (101.81 mg,0.736 mmol, 1.00 eq.). The mixture was de-gassed and heated to 120° C.for 24 hours under N₂. TLC (Petroleum ether/Ethyl acetate=1:1) showedthe starting material was consumed completely. The reaction mixture waspoured into H₂O (20 mL) and extracted with ethyl acetate (50 mL×3). Theorganic phase was washed with brine (30 mL), dried over anhydrousNa₂SO₄, concentrated, and purified by a silica gel column chromatography(Petroleum ether/Ethyl acetate=2:1 to 1:1) to give ethyl54(2-(tert-butylthio)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(200.00 mg, 0.48 mmol, 65.18% yield,) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.34 (s, 1H), 8.29 (br. s., 1H), 7.60 (dd, J=5.9, 8.4 Hz,1H), 7.00 (t, J=7.7 Hz, 1H), 6.29 (br. s., 2H), 5.00 (br. s., 2H), 4.37(d, J=6.8 Hz, 2H), 3.41 (br. s., 3H), 1.36-1.20 (m, 12H).

Step 2. To a solution of ethyl5-((2-(tert-butylthio)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(300.00 mg, 0.720 mmol, 1.00 eq.) in DCM (8.00 mL) was added BBr₃(902.21 mg, 3.60 mmol, 5.00 eq.) drop-wise at 0° C. under N₂. Themixture was stirred at 0° C. for 2.5 hours. TLC (Petroleum ether: Ethylacetate=1:1) showed the reaction was completed. The mixture was pouredinto water (20 mL). The aqueous phase was extracted with dichloromethane(50 mL×3). The combined organic phase was washed with brine (30 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by pre-HPLC (Column: Phenomenex Synergi C18 150*30mm*4 um and Condition: 0.05% HCl-ACN) and lyophilized to afford A17 HClsalt (38.00 mg, 0.098 mmol, 13.61% yield) as a white solid.

Example A18

Step 1. The mixture of 2-bromo-4-fluorophenol (10.00 g, 52.36 mmol, 1.00eq.), trifluoro(vinyl)-borane potassium salt (9.84 g, 66.50 mmol, 1.27eq.), Cs₂CO₃ (51.18 g, 157.08 mmol, 3.00 eq.) and Pd(PPh₃)₂Cl₂ (1.84 g,2.62 mmol, 0.05 eq.) in THF (90.00 mL) and H₂O (10.00 mL) was de-gassedand then heated to 90° C. for 12 hours under N₂. TLC (Petroleumether/Ethyl acetate=10/1) showed the starting material was consumedcompletely. The reaction mixture was poured into H₂O (100 mL). Themixture was extracted with ethyl acetate (300 mL×3). The organic phasewas washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄,concentrated, and purified with a silica gel column chromatography(eluted by EtOAc/Petroleum ether=1/30) to afford 4-fluoro-2-vinylphenol(3.50 g, 25.34 mmol, 48.39% yield) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.12 (dd, J=3.0, 9.5 Hz, 1H), 6.89-6.81 (m, 1H), 6.79-6.73 (m,1H), 5.75 (d, J=17.6 Hz, 1H), 5.64 (s, 1H), 5.39 (d, J=11.3 Hz, 1H).

Step 2. The mixture of 4-fluoro-2-vinylphenol (1.95 g, 14.12 mmol, 1.00eq.), TBSCl (6.38 g, 42.35 mmol, 3.00 eq.) and 1H-imidazole (5.77 g,84.70 mmol, 6.00 eq.) in DCM (20.00 mL) was stirred at 20° C. for 5hours under N₂. TLC (Petroleum ether/Ethyl acetate=10:1) showed thestarting material was consumed completely. The reaction mixture waspoured into H₂O (30 mL). The mixture was extracted with dichloromethane(50 mL×3). The organic phase was washed with brine (50 mL), dried overanhydrous Na₂SO₄, concentrated, and purified by a silica gel columnchromatography eluted with petroleum ether to affordtri-butyl(4-fluoro-2-vinylbenzyl)silane (2.30 g, 9.11 mmol, 64.54%yield) as a colorless oil.

Step 3. The mixture of tri-butyl(4-fluoro-2-vinylbenzyl)silane (2.30 g,9.11 mmol, 1.00 eq.), ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.06 g, 9.11 mmol, 1.00eq.), Pd(PhCN)₂Cl₂ (118.20 mg, 0.455.63 mmol, 0.05 eq.) andtris-o-tolylphosphane (277.36 mg, 0.911 mmol, 0.10 eq.), DIPEA (7.07 g,54.68 mmol, 6.00 eq.) in DMF (25.00 mL) was de-gassed and then heated to120° C. for 24 hours under N₂. TLC (Petroleum ether/Ethyl acetate=1:1)showed the starting material was consumed completely. The reactionmixture was poured into H₂O (30 mL). The mixture was extracted withethyl acetate (100 mL×3). The organic phase was washed with saturatedbrine (30 mL), dried over anhydrous Na₂SO₄, concentrated, and purifiedby a silica gel column chromatography (EtOAc: petroleum ether=1:3) toafford ethyl(E)-5-(5-fluoro-2-hydroxystyryl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(1.00 g, 2.26 mmol, 24.86% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 9.29 (br. s., 1H), 8.50 (d, J=7.0 Hz, 1H), 8.28 (br. s., 1H),7.84 (d, J=16.6 Hz, 1H), 7.20-7.04 (m, 3H), 6.69 (d, J=5.8 Hz, 2H), 4.20(q, J=6.9 Hz, 2H), 1.30-1.19 (m, 3H).

Step 4. To a mixture of ethyl(E)-5-(5-fluoro-2-hydroxystyryl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(378.22 mg, 1.04 mmol, 1.00 eq.) and 4-methylbenzenesulfonohydrazide(3.29 g, 17.68 mmol, 17.00 eq.) in THF (4.00 mL) was added NaOAc (1.71g, 20.80 mmol, 20.00 eq.) in one portion at 20° C. under N₂. The mixturewas then heated to 65° C. and stirred for 12 hours. TLC showed thereaction was completed. The mixture was cooled to 20° C. andconcentrated under reduced pressure at 45° C. Water (100 mL) was addedto the residue. The aqueous phase was extracted with ethyl acetate (300mL×2). The combined organic phase was washed with saturated brine (50mL), dried with anhydrous Na₂SO₄, filtered, concentrated in vacuum, andpurified by pre-HPLC (Column: Phenomenex Synergi Max-RP 250*50 mm*10 um,0.225% FA-ACN) to afford A18 (120.00 mg, 0.347 mmol, 33.42% yield) as awhite solid.

Example A20

To a mixture of 4-fluoro-2-methylaminomethyl-phenol (305.2 mg, 1.97mmol) and 6-chloro-imidazo[1,2-b]pyridazine-3-carboxylic acid ethylester (230 mg, 1.02 mmol) in DMSO (5 mL) was added KF (180 mg, 3.01mmol). The reaction mixture was stirred at 120° C. for 18 hours undernitrogen. The solution was then cooled to ambient temperature, dilutedwith water (20 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layers were further washed with water (3×50 mL) and brine (50mL), dried over Na₂SO₄ and concentrated. The residue was then purifiedby a silica gel column eluting with EtOAc/hexane (0-50%, 10 CV) toafford the desired product as a white solid (240 mg, 69%).

Example A22

A21-1 was prepared according to the General Method A. To a solution ofA22-1 (150 mg, 0.387 mmol) in ethanol (2 mL) was added 4M HCl in dioxane(2 mL) and the reaction solution was heated at 75° C. for 2 hours Thesolvents were evaporated and the residue was neutralized with Et3N andpurified on a silica gel cartridge eluting with methanol/CH₂Cl₂(0-12.5%) to provide A22 (144 mg, 100%).

Example A23

Step 1. To a mixture of (5-fluoro-2-methoxyphenyl)methanethiol (496.1mg, 2.88 mmol) and 6-chloro-imidazo[1,2-b]pyridazine-3-carboxylic acidethyl ester (650.0 mg, 2.88 mmol) in ethanol (14.4 mL) was added DIPEA(1.12 g, 8.64 mmol). The reaction mixture was stirred at 80° C. for 1hour. The solution was cooled to ambient temperature, diluted with water(50 mL) and extracted with DCM (3×50 mL). The combined extracts weredried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified with flash chromatography (ISCO system, silica (120 g)eluting with EtOAc/hexane (0-50%) to afford A23-2 (560 mg, 54% yield).A23-2 was crash out of column during purification.

Step 2. To a solution of A23-2 (498.7 mg, 1.38 mmol) in methanol (100mL) was added 4M HCl in dioxane (10 mL) and the reaction solution washeated at 75° C. for 2 hours The solvents were evaporated and theresidue was neutralized with Et3N and purified on a silica gel cartridgeeluting with methanol/CH₂Cl₂ (0-12.5%) to provide A23 (470 mg, 98%).

A1-A24 were prepared according to the General Method A and the methodsdescribed herein.

Example Structure Name Analytical Data A1

ethyl 5-((5-fluoro-2- hydroxybenzyl)(methyl) amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate MS: 345.2 (M + H)⁺; ¹H NMR (500 MHz,Chloroform-d) δ 9.71 (bs, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H),6.98- 6.87 (m, 3H), 6.37 (d, J = 7.9 Hz, 1H), 4.82 (s, 2H), 4.42 (q, J =7.1 Hz, 2H), 3.21 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). A2

ethyl 5-(ethyl(5- fluoro-2- hydroxybenzyl)amino) pyrazolo[1,5-a]pyrimidine-3- carboxylate MS: 359.3 (M + H)⁺; ¹H NMR (300 MHz,Chloroform-d) δ 9.75 (bs, 1H), 8.30-8.27 (m, 2H), 6.95-6.86 (m, 3H),6.34 (d, J = 7.9 Hz, 1H), 4.79 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.56(q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H).A3

ethyl 5-((5-fluoro-2- hydroxybenzyl)amino) pyrazolo[1,5- a]pyrimidine-3-carboxylate MS: 331.3 (M + H)⁺; ¹H NMR (300 MHz, Chloroform-d) δ 9.61(bs, 1H), 8.52 (d, J = 7.5 Hz, 1H), 8.28 (bt, J = 5.1 Hz, 1H), 8.13 (s,1H), 7.25-7.23 (m, 1H), 6.93-6.86 (m, 1H), 6.81-6.77 (m, 1H), 6.44 (d, J= 7.5 Hz, 1H), 4.51 (d, J = 5.1 Hz, 2H), 4.20 (q, J = 6.9 Hz, 2H), 1.39(t, J = 6.9 Hz, 3H). A4

ethyl 5-((2- hydroxybenzyl)(methyl) amino)pyrazolo [1,5-a]pyrimidine-3-carboxylate MS: 327.5 (M + H)⁺; ¹H NMR (300 MHz, Chloroform-d) δ 9.79(s, 1H), 8.30-8.27 (m, 2H), 7.26-7.21 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H),6.84 (t, J = 7.5 Hz, 1H), 6.34 (d, J = 8.1 Hz, 1H), 4.85 (s, 2H), 4.42(q, J = 6.9 Hz, 2H), 3.18 (s, 3H), 1.40 (t, J = 6.9 Hz, 3H). A5

ethyl 5-((5-fluoro-2- hydroxybenzyl)(2- hydroxy-2- methylpropyl)amino)pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 403.2 (M + H)⁺; ¹H NMR(400 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H),7.05-6.80 (m, 3H), 6.59 (br. s., 1H), 5.06 (br. s., 2H), 4.43 (q, J =7.1 Hz, 2H), 3.62 (br. s., 2H), 1.60 (s, 1H), 1.46- 1.36 (m, 9H). A6

ethyl 5-((5-fluoro-2- hydroxybenzyl)(1- methylpyrrolidin-3-yl)amino)pyrazolo [1,5-a]pyrimidine-3- carboxylate MS: 414.2 (M + H)⁺;¹H NMR (400 MHz, Chloroform-d) δ 8.67 (br. s., 2H), 8.35 (d, J = 8.0 Hz,1H), 8.24 (s, 1H), 7.14- 7.07 (m, 1H), 6.83 (dt, J = 2.8, 8.4 Hz, 1H),6.73 (br. s., 1H), 6.60 (br. s., 1H), 5.13 (br. s., 1H), 4.75-4.62 (m,2H), 4.34 (q, J = 6.9 Hz, 2H), 3.88 (br. s., 3H), 3.41 (br. s., 1H),3.04 (br. s., 3H), 2.54 (br. s., 2H), 1.40 (t, J = 7.2 Hz, 3H). A7

ethyl 5-((1-(5- fluoro-2- hydroxyphenyl)ethyl) amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate MS: 345.3 (M + H)⁺; ¹H NMR (300 MHz,Chloroform-d) δ 9.61 (bs, 1H), 8.24 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H),6.96- 6.91 (m, 2H), 6.88-6.81 (m, 1H), 6.09 (d, J = 7.8 Hz, 1H),5.72-5.63 (m, 1H), 5.45 (bd, J = 8.7 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H),1.64 (d, J = 6.9 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H). A8

ethyl (R)-5-((1-(5- fluoro-2- hydroxyphenyl)ethyl) amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate MS: 345.2 (M + H)⁺. A9

ethyl 5-((1-(5- fluoro-2- hydroxyphenyl)propyl) amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate MS: 359.2 (M + H)⁺; ¹H NMR (400 MHz,Chloroform-d) δ 8.99 (br. s., 1H), 8.27 (s, 1H), 8.20 (d, J = 7.5 Hz,1H), 6.98 (dd, J = 5.0, 8.8 Hz, 1H), 6.94- 6.84 (m, 2H), 6.13 (d, J =7.5 Hz, 1H), 5.41 (br. s., 2H), 4.57- 4.40 (m, 2H), 2.11-1.95 (m, 2H),1.44 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H). A10

ethyl 5-((1-(5- fluoro-2- hydroxyphenyl)-2- methylpropyl)amino)pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 373.2 (M + H)⁺; ¹H NMR(400 MHz, Chloroform-d) δ 8.25 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H), 6.99(dd, J = 5.1, 8.7 Hz, 1H), 6.91-6.81 (m, 2H), 6.14 (d, J = 7.5 Hz, 1H),5.11 (t, J = 9.7 Hz, 1H), 4.62-4.37 (m, 2H), 2.22 (qd, J = 6.5, 17.1 Hz,1H), 1.43 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.5 Hz, 3H), 0.89 (d, J =6.5 Hz, 3H). A11

ethyl 5- ((cyclopropyl(5- fluoro-2- hydroxyphenyl)methyl)amino)pyrazolo[1,5-a] pyrimidine-3- carboxylate MS: 371.2 (M + H)⁺; ¹HNMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H),7.13 (dd, J = 3.0, 9.4 Hz, 1H), 7.00-6.94 (m, 1H), 6.91- 6.84 (m, 1H),6.14 (d, J = 7.7 Hz, 1H), 5.69 (d, J = 8.0 Hz, 1H), 4.70 (t, J = 8.3 Hz,1H), 4.49-4.38 (m, 2H), 1.42 (t, J = 7.1 Hz, 4H), 0.83-0.74 (m, 1H),0.72-0.63 (m, 1H), 0.57 (qd, J = 4.8, 9.6 Hz, 1H), 0.48- 0.40 (m, 1H).A12

ethyl 5- ((cyclobutyl(5- fluoro-2- hydroxyphenyl)methyl)amino)pyrazolo[1,5-a] pyrimidine-3- carboxylate MS: 385.2 (M + H)⁺; ¹HNMR (400 MHz, Chloroform-d) δ 9.09 (br. s., 1H), 8.27 (s, 1H), 8.20 (d,J = 7.5 Hz, 1H), 6.98 (dd, J = 5.0, 8.8 Hz, 1H), 6.91- 6.78 (m, 2H),6.12 (d, J = 7.5 Hz, 1H), 5.45 (t, J = 9.4 Hz, 1H), 5.27 (d, J = 8.4 Hz,1H), 4.51-4.45 (m, 2H), 2.98- 2.89 (m, 1H), 2.29 (dd, J = 3.8, 7.5 Hz,1H), 2.07-1.90 (m, 4H), 1.75-1.66 (m, 1H), 1.45 (t, J = 7.1 Hz, 3H). A13

ethyl 5-((2- cyclopropyl-1-(5- fluoro-2- hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a] pyrimidine-3- carboxylate MS: 385.2 (M + H)⁺; ¹HNMR (400 MHz, Chloroform-d) δ 9.00 (br. s., 1H), 8.27 (s, 1H), 8.19 (d,J = 7.5 Hz, 1H), 7.00- 6.82 (m, 3H), 6.15 (d, J = 7.5 Hz, 1H), 5.57 (br.s., 2H), 4.52- 4.40 (m, 2H), 2.01-1.77 (m, 2H), 1.44 (t, J = 7.2 Hz,3H), 0.72 (d, J = 6.5 Hz, 1H), 0.56- 0.41 (m, 2H), 0.24-0.07 (m, 2H).A14

ethyl 5-(((5-fluoro- 2-hydroxyphenyl) (phenyl)methyl)amino)pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 407.2 (M + H)⁺; ¹H NMR(400 MHz, Chloroform-d) δ 9.66 (s, 1H), 8.64-8.55 (m, 2H), 8.16 (s, 1H),7.33 (d, J = 4.4 Hz, 4H), 7.25 (qd, J = 4.3, 8.5 Hz, 1H), 7.11 (dd, J =3.1, 9.7 Hz, 1H), 6.98-6.91 (m, 1H), 6.88-6.78 (m, 2H), 6.58 (d, J = 7.5Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.1 Hz, 4H). A15

ethyl 5-((1-(5- chloro-2- hydroxyphenyl)ethyl) amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate MS: 361.2 (M + H)⁺; ¹H NMR (400 MHz,Chloroform-d) δ 9.42 (br. s., 1H), 8.27 (s, 1H), 8.20 (d, J = 7.5 Hz,1H), 7.28 (s, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 2.5, 8.8 Hz,1H), 6.95 (d, J = 8.5 Hz, 1H), 6.11 (d, J = 7.5 Hz, 1H), 5.75- 5.64 (m,1H), 5.46 (d, J = 8.3 Hz, 1H), 4.52-4.40 (m, 2H), 1.68 (d, J = 6.8 Hz,3H), 1.61 (s, 2H), 1.44 (t, J = 7.2 Hz, 3H). A16

ethyl 5-((1-(5- fluoro-2- hydroxyphenyl)ethyl) (methyl)amino)pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 359.2 (M + H)⁺; ¹H NMR(400 MHz, Chloroform-d) δ 9.61 (s, 1H), 8.35-8.29 (m, 2H), 7.08-7.03 (m,1H), 6.92 (dd, J = 1.3, 6.1 Hz, 2H), 6.45 (q, J = 6.9 Hz, 1H), 6.35 (d,J = 7.9 Hz, 1H), 4.51-4.36 (m, 2H), 3.00 (s, 3H), 1.65 (d, J = 7.0 Hz,3H), 1.41 (t, J = 7.2 Hz, 3H). A17

ethyl 5-((5-fluoro-2- mercaptobenzyl) (methyl)amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate MS: 361.2 (M + H)⁺; ¹H NMR (400 MHz,Chloroform-d) δ 9.19 (br. s., 1H), 9.09 (d, J = 7.3 Hz, 1H), 8.51 (s,1H), 7.91-7.81 (m, 2H), 7.48 (dt, J = 2.8, 8.5 Hz, 1H), 7.14 (d, J = 7.3Hz, 1H), 4.29 (br. s., 2H), 4.18 (q, J = 7.0 Hz, 2H), 2.56 (br. s., 3H),1.16 (t, J = 7.2 Hz, 3H). A18

ethyl 5-(5-fluoro-2- hydroxyphenethyl) pyrazolo[1,5- a]pyrimidine-3-carboxylate MS: 330.2 (M + H)⁺; ¹H NMR (400 MHz, Chloroform-d) δ 9.42(s, 1H), 9.14 (d, J = 7.0 Hz, 1H), 8.55 (s, 1H), 7.18 (d, J = 7.0 Hz,1H), 7.05 (dd, J = 3.0, 9.5 Hz, 1H), 6.86-6.80 (m, 1H), 6.79-6.74 (m,1H), 4.30 (q, J = 7.2 Hz, 2H), 3.21-3.13 (m, 2H), 3.06-2.99 (m, 2H),1.33 (t, J = 7.2 Hz, 3H). A19

ethyl 5-((5-fluoro-2- hydroxybenzyl) (methyl)amino)-2-methylpyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 359.2 (M + H)⁺. A20

ethyl 6-((5-fluoro-2- hydroxybenzyl) (methyl)amino)imidazo[1,2-b]pyridazine-3- carboxylate MS: 345.2 (M + H)⁺; ¹H NMR (500 MHz,Chloroform-d) δ 8.61 (s, 1H), 8.17 (s, 1H), 7.91 (d, J = 10.0 Hz, 1H),7.00- 6.86 (m, 4H), 4.78 (s, 2H), 4.47 (qd, J = 7.2, 0.5 Hz, 2H), 3.17(s, 3H), 1.41 (td, J = 7.1, 0.5 Hz, 3H). A21

ethyl 5-(((5-fluoro- 2-hydroxypyridin-3- yl)methyl)(methyl)amino)pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 346.2 (M + H)⁺. A22

ethyl 5-(((5-fluoro- 2-hydroxypyridin-3- yl)methyl)(isopropyl)amino)pyrazolo[1,5-a] pyrimidine-3- carboxylate MS: 374.2 (M + H)⁺. A23

ethyl 5-((5-fluoro-2- hydroxybenzyl)thio) pyrazolo[1,5- a]pyrimidine-3-carboxylate MS: 348.2 (M + H)⁺. A24

ethyl 5-((1-(5- fluoro-2- hydroxyphenyl)-2- hydroxyethyl)amino)pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 361.2 (M + H)⁺.

Example B7

Step 1. To a mixture of 1-(5-fluoro-2-hydroxy-phenyl)-ethanone (773 mg,5.0 mmol) and (2-chloro-ethyl)-carbamic acid tert-butyl ester (1.80 g,10.0 mmol) in DMF (20 mL) were added KI (2.0 mg, 0.012 mmol) and Cs₂CO₃(3.26 g, 10.0 mmol). The mixture was stirred at 80° C. overnight. Themixture was then cooled to ambient temperature, diluted with EtOAc, andwashed with 1N NaOH (5×10 mL) until LCMS showed no1-(5-fluoro-2-hydroxy-phenyl)-ethanone peak. The organic layer was driedover Na₂SO₄ and concentrated. The residue was then purified by a silicagel column eluting with EtOAc/hexane (0-30%, 10 CV) to afford thedesired product B7-2 as a yellowish solid (1.1 g, 73.8%): LC-MS (ESI)m/z 320.3 (M+Na)⁺.

Step 2. To a solution of B7-2 (1.0 g, 3.36 mmol) in MeOH (10 mL) wasadded NaBH₄ (640 mg, 16.8 mmol) in portion wise. The mixture was stirredat ambient temperature for 2 h until no starting material left by LCMS.The solution was then diluted with water (50 mL) and extracted with DCM(3×20 mL). The combined DCM layers were dried over Na₂SO₄ andconcentrated. The residue was purified by a silica gel column elutingwith EtOAc/hexane (0-50%, 10 CV) to afford the desired product B7-3 as apale yellow solid (0.75 g, 75%). LC-MS (ESI) m/z 322.3 (M+Na)⁺; ¹H NMR(500 MHz, Chloroform-d) δ 7.11 (dd, J=9.2, 3.4 Hz, 1H), 6.89 (ddd,J=9.0, 7.9, 3.2 Hz, 1H), 6.77 (dd, J=8.9, 4.4 Hz, 1H), 5.09 (q, J=6.6Hz, 1H), 4.92 (d, J=4.4 Hz, 1H), 4.03 (t, J=5.2 Hz, 2H), 3.62-3.50 (m,2H), 1.49 (d, J=6.4 Hz, 3H), 1.45 (s, 9H).

Step 3: To a solution of B7-3 (600 mg, 2.0 mmol) and{2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-ethyl}-carbamic acidtert-butyl ester (450 mg, 2.0 mmol) in dry THF (40.0 mL) at −78° C. wasadded NaH (60%, 80 mg, 2.0 mmol) in portion. The suspension was stirredat −78° C. for 4 h and allowed to warm to 0° C. and stirred foradditional 4 h. The mixture was then put in the freezer at −20° C.overnight. LC-MS showed a good conversion to the desired product. Themixture was then quenched with a mixture of ice and 1N HCl and extractedwith EtOAc (3×20 mL). The organic layer was dried over Na₂SO₄,concentrated and purified twice to afford the desired product B7 as ayellow solid (240 mg, 25%):

B1-B7 were prepared according to the General Method B and methodsdescribed herein.

Example Structure Name Analytical Data B1

ethyl 5-((2-(2-((tert- butoxycarbonyl) amino)ethoxy)-5-fluorobenzyl)(methyl) amino)pyrazolo [1,5-a]pyrimidine-3- carboxylateMS: 488.3.1 (M + H)⁺; ¹H NMR (500 MHz, Chloroform-d) δ 8.30 (s, 1H),8.26 (s, 1H), 6.92 (td, J = 8.6, 3.3 Hz, 1H), 6.83- 6.76 (m, 1H), 6.31(s, 1H), 4.93 (s, 2H), 4.51-4.44 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.03(t, J = 4.9 Hz, 2H), 3.69- 3.63 (m, 1H), 3.51 (s, 2H), 3.30 (s, 2H),1.44 (s, 9H), 1.41- 1.35 (t, J = 7.2 Hz, 3H). B2

ethyl 5-((2-(2-((tert- butoxycarbonyl) amino)ethoxy)-5-fluorobenzyl)(ethyl) amino)pyrazolo[1,5- a]pyrimidine-3- carboxylate MS:502.2 (M + H)⁺. B3

ethyl 5-((2-(2-((tert- butoxycarbonyl) amino)ethoxy)-5-fluorobenzyl)(propyl) amino)pyrazolo[1,5- a]pyrimidine-3- carboxylateMS: 516.3 (M + H)⁺. B4

ethyl 5-((2-(2-((tert- butoxycarbonyl) amino)ethoxy)-5- fluorobenzyl)(cyclopropyl)amino) pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 514.2(M + H)⁺. B5

ethyl 5-((2-(2-((tert- butoxycarbonyl) amino)ethoxy)-5- fluorobenzyl)(2-hydroxyethyl)amino) pyrazolo[1,5- a]pyrimidine-3- carboxylate MS: 518.3(M + H)⁺. B6

ethyl 5-((6-(2-((tert- butoxycarbonyl) amino)ethoxy)-2- chloro-3-fluorobenzyl)(methyl) amino)pyrazolo[1,5- a]pyrimidine-3- carboxylateMS: 522.5 (M + H)⁺. B7

ethyl 6-(1-(2-(2- ((tert- butoxycarbonyl) amino)ethoxy)-5-fluorophenyl)ethoxy) imidazo[1,2- b]pyridazine-3- carboxylate LC-MS(ESI) m/z 511.6 (M + Na)⁺; ¹H NMR (500 MHz, Chloroform-d) δ 8.16 (s,1H), 7.90 (d, J = 9.7 Hz, 1H), 7.16 (dd, J = 9.0, 3.2 Hz, 1H), 0.95 (d,J = 9.5 Hz, 1H), 6.90-6.88 (m, 1H), 6.81-6.78 (m, 1H), 6.68 (q, J = 6.2Hz, 1H), 5.84- 5.68 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.15-4.09 (m,2H), 3.60-3.52 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 7.2 Hz,3H), 1.35 (s, 9H).

Examples 2 and 2-1

Synthesis A:

Example 2 may be prepared as shown in the following scheme, startingwith racemic or enantiomeric ally enriched starting materials:

Step 1. To a mixture of compounds 2A (1 equiv.) and 2B (1.2 equiv.) inanhydrous DMF (0.2 M) is added Cs₂CO₃ (1.5 equiv.) and the reaction isheated in an oil bath at 80° C. under nitrogen overnight. The mixture iscooled, poured into water, and extracted with EtOAc three times. Thecombined organic layers are washed with water five times, washed withbrine, and dried over Na₂SO₄. After condensation, the residue ispurified on a flash column eluting with EtOAc/Hexanes to providecompound 2C.

Step 2. To a solution of compound 2C (1 equiv.) in anhydrous THF (0.2 M)is added NaH (1.2 equiv.). The reaction mixture is stirred at ambienttemperature for 0.5 hours. To the mixture is added compound 2D and thereaction is heated at reflux under nitrogen overnight. The reaction iscooled to ambient temperature and diluted with a portion of water (1/3of THF volume) and NaOH (3 equiv.). The mixture is stirred and heated at70° C. for 2 hours or until the ester is completely hydrolyzed to thecorresponding acid. After cooling, the organic layer is separated andthe water layer is neutralized to pH-5. The resulting precipitate isfiltered, washed with water three times, and dried under vacuum toprovide compound 2E, which is used without further purification.

Step 3. To a solution of compound 2E (1 equiv.) in CH₂Cl₂ (0.2 M) isadded 4 M HCl/dioxane (10 equiv.) and the mixture is stirred untilcompound 2E is completely converted to compound 2F. The mixture isconcentrated, and the residue is purified by reverse phase preparativeHPLC to provide compound 2F.

Step 4. A solution of compound 2F (1 equiv.) and DIPEA (10 equiv.) inDMF (0.2 M) is added drop-wise to a solution of HATU (1.4 equivalent) inDMF (0.1 M) at 0° C. After addition is complete, the mixture is stirredat 0° C. for a further 30 min. Water is added and the mixture isextracted with EtOAc three times. The combined organic layers are washedwith saturated NaHCO₃ twice, then with brine, dried over Na₂SO₄, andconcentrated. The residue is purified on a silica gel column elutingwith EtOAc/Hexanes to provide Example 2.

Synthesis B:

Examples 2 and 2-1 may also be prepared according to the followingscheme, using racemic or enantiomerically enriched starting materials:

Step 1. Compound 2C is reacted with compound 2G under the conditionsdescribed in Synthesis A, Step 2, to provide compound 2H.

Step 2. Compound 2H is converted to compound 21 under the conditionsdescribed in Synthesis A, Step 3.

Step 3. To a solution of compound 21 (1 equiv.) and DIPEA (2 equiv.) intoluene (0.01 M) is added Pd(P-tBu₃)₂ (1 equiv.). The reaction mixtureis heated at 100° C. under 4 bar CO overnight, and then concentrated.The residue is purified on a silica gel column eluting withEtOAc/hexanes to provide Example 2.

Examples 10 and 10-1

Examples 10 and 10-1 may be prepared as shown in the following schemeusing racemic or enantiomerically enriched starting materials:

Step 1. Compound 10C is prepared from compounds 10A and 10B using themethod described in Example 2, Synthesis A, Step 1.

Step 2. Compound 10E is prepared from compounds 10C and 10D using themethod described in Example 2, Synthesis A, Step 2.

Step 3. A mixture of compound 10E (1 equiv.) and NH₂—NH₂ (10 equiv.) inmethanol (0.2 M) is heated at reflux until compound 10E is completelyconverted to compound 10F. The mixture is concentrated and the residueis purified in a reverse phase preparative HPLC to provide compound 10F.

Step 4. Compound 10F is converted into Example 10 according to themethod described for Example 2, Synthesis A, Step 4.

Example 11-1

Step 1: To a solution of 2-chloro-3-fluoro-6-hydroxy-benzaldehyde (175mg, 1.0 mmol), bis-tos ethylene glycol (740 mg, 2.0 mmol) in ACN (5 mL),K₂CO₃ (276 mg, 2.0 mmol) and KI (2 mg) was added. The reaction mixturewas stirred at 120° C. for 24 hours The solid was filtered off and thefiltrate was concentrated and purified by column chromatography toafford the desired product 11-1B as a white solid. The material was useddirectly in the next step.

Step 2: To a solution of 11-1B (373 mg, 1 mmol) in ACN (5 mL), NaN₃ (650mg, 10 mmol) was added and the mixture was stirred at 120° C. for 24hours The solid was filtered off and the residue was concentrated andpurified by column chromatography to afford 11-1C as a white solid (200mg, 82%). ¹H NMR (500 MHz, Chloroform-d) δ 10.49 (d, J=1.1 Hz, 1H), 7.31(dd, J=9.2, 8.2 Hz, 1H), 6.88 (dd, J=9.2, 3.7 Hz, 1H), 4.21 (dd, J=5.4,4.5 Hz, 2H), 3.67 (dd, J=5.4, 4.5 Hz, 2H).

Step 3: To a solution of 11-1C (100 mg, 0.41 mmol) in anhydrous THF (5mL) at −78° C., methyl magnesium bromide (1N in Et₂O, 0.82 mL, 0.82mmol) was added. The mixture was allowed to warm to room temperature andstirred for 2 hours until TLC shows no starting material present. Thesolution was then cooled to 0° C. and quenched with sat. aq NH₄OAc andextracted with EtOAc (20 mL×3). The combined organic was dried overNa₂SO₄ and concentrated. The residue 11-1D was used directly in the nextstep. ¹H NMR (500 MHz, Chloroform-d) δ 6.97 (dd, J=9.2, 8.3 Hz, 1H),6.77 (dd, J=9.1, 4.1 Hz, 1H), 5.27 (q, J=6.7 Hz, 1H), 4.34-4.29 (m, 1H),4.22-4.16 (m, 1H), 4.04-3.98 (m, 1H), 3.95-3.88 (m, 2H), 1.51 (d, J=6.7Hz, 3H).

Step 4: To a solution of 5-Chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid ethyl ester (100 mg, 0.44 mmol) and 11-1D (110 mg, 0.41 mmol) inanhydrous THF (5.0 mL) at −78° C., NaH (60%, 17 mg, 0.44 mmol) wasadded. The mixture was allowed to warm to rt and stirred for 8 hoursuntil a good amount of desired product was formed. The mixture was thendiluted with water/ice and extracted with DCM (3×20 mL). The organiclayer was dried over Na₂SO₄, concentrated and purified by silica gelcolumn chromatography to afford 11-1E as a yellow liquid (20 mg, 0.045mmol, 6%), which is used directly in the next step.

Step 5: To a solution of 11-1E (20 mg, 0.045 mmol) in MeOH (1 mL), LiOH(16 mg, 0.38 mmol) was added, followed by 1 mL of H₂O. The mixture wasallowed to stir at 60° C. for 4 hours until LCMS and TLC shows thereaction was complete. The solution was cooled to rt, partiallyconcentrated and acidified by 1N HCl until pH 2-3. The aqueous mixturewas extracted with DCM (3×10 mL). The organic layer was dried overNa₂SO₄ and concentrated. The residue 11-1F was used directly in the nextstep.

Step 6: To a solution of 11-1F (20 mg, 0.045 mmol) in DCM (5 mL), PPh₃(24 mg, 0.09 mmol) was added. The solution was stirred for 1 hr untilTLC shows a complete conversion of the starting material to the desiredproduct. The mixture was then used directly in the next step withoutfurther characterization. 11-1G MS ESI⁺ m/z 417.7 (M+Na)⁺.

Step 7: To a solution of 11-1G obtained from previous step in DMF (10mL), DIPEA (0.20 mL, 1.15 mmol) was added. The solution was chilled withdry ice/acetone bath and HATU (40.0 mg, 0.11 mmol) was added. Thesolution was allowed to warm to rt slowly and LCMS shows a cleantransformation of the starting material to the desired product. Themixture was then diluted with water (50 mL) and extracted with EtOAc(3×50 mL). The combined organic layer was washed with water (3×50 mL)and brine (50 mL) and dried over Na₂SO₄. The solvent was removed and theresulting residue was purified by silica column chromatography (0-5%MeOH/DCM) afford the desired product as a white solid (2.6 mg, 20%yield).

Examples 14 and 14-1

Examples 14 and 14-1 may be prepared according to the following schemeusing racemic or enantiomerically enriched starting materials:

Step 1. To a mixture of compounds 14A (1 equiv.) and 14B (1.2 equiv.) inanhydrous DMF (0.2 M) is added Cs₂CO₃ (1.5 equiv.) and the reaction isheated in an oil bath at 80° C. under nitrogen overnight. The mixture iscooled, poured into water, and extracted with EtOAc three times. Thecombined organic layers are washed with water five times, washed withbrine, and dried over Na₂SO₄. After condensation, the residue ispurified on a flash silica gel column eluting with EtOAc/Hexanes toprovide 14C.

Step 2. To a cooled (−78° C.) solution of 14C (1 equiv.) in anhydrousTHF (0.2 M) is added MeMgBr (3 equiv, 3 M in diethyl ether). Thereaction is stirred for 2 h from −78° C. to 0° C., and quenched withsaturated aqueous NH₄Cl, and then extracted with EtOAc (2×). Theorganics are dried over MgSO₄, filtered and concentrated. This residueis purified by a silica gel column chromatography eluting withEtOAc/Hexanes to afford 14D.

Step 3. To a solution of compound 14D (1 equiv.) in anhydrous THF (0.2M) is added NaH (1.2 equiv.). The reaction mixture is stirred at ambienttemperature for 0.5 hours. To the mixture is added 14E and the reactionis heated to reflux under nitrogen overnight. The reaction is cooled toambient temperature, and then poured into water. The product isextracted with EtOAc three times. The combined organics are washed withbrine, dried over Na₂SO4, and concentrated. The residue is purified witha silica gel column eluting with EtOAc/Hexanes to provide the product14F.

Step 4. To a solution of compound 14F (1 equiv.) in CH₂Cl₂ (0.2 M) isadded 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until allof 14F is converted to 14G. After concentration, the residue is purifiedin a reverse phase preparative HPLC to provide 14G.

Step 5. To a solution of 14G (1 equiv.) and DIPEA (2 equiv.) in toluene(0.01 M) is added Pd(P-t-Bu₃)₂ (1 equiv.). The reaction mixture isheated at 100° C. under 4 bar CO overnight, and then concentrated. Theresidue is purified on a silica gel column eluting with EtOAc/hexanes toprovide 14.

Examples 15 and 15-1

Examples 15 and 15-1 may be prepared according to the following schemeusing racemic or enantiomerically enriched starting materials:

Step 1. To a suspension of 15A (1.0 equiv.) in THF (0.15 M) is added asolution of 2.0 M aqueous NaOH (3 equiv.). The homogeneous reactionmixture is stirred overnight, and then the organics are removed underreduced pressure. The aqueous residue is brought to pH-4 with 1.0 Maqueous HCl. The resulting precipitate is collected by filtration andrinsed with H₂O to afford a solid of 15B. The filtrate is extracted withEtOAc (2×), and the organics are concentrated under reduced pressure toprovide an additional portion of 15B.

Step 2. A stock solution of Jones reagent (2.67 M) is prepared bycarefully adding concentrated H₂SO₄ (2.3 mL) to CrO₃ (2.67 g) and thendiluting to 10 mL with H₂O. To a suspension of 15B (1.0 equiv.) inacetone (0.067 M) is slowly added Jones reagent (1.2 equiv.). Thereaction mixture is stirred for 15 min and then quenched with i-PrOH andfiltered through a pad of diatomaceous earth, rinsing with acetone. Thefiltrate is concentrated to provide 15C which is used without furtherpurification.

Step 4. To a solution of 15C (1.0 equiv.) in DMF (0.40 M) at 0° C. isadded NaH (60% in mineral oil, 1.5 equiv.). The reaction mixture isstirred at room temperature for 30 min and then cooled back to 0° C.,and 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 1.2 equiv.) isslowly added. The reaction mixture is warmed to room temperature,stirred for 1 h, and then quenched with H₂O and extracted with EtOAc(3×). The combined organics are washed with H₂O (3×) and brine, and thendried over MgSO₄ and concentrated. The residue is purified by a flashsilica-gel chromatography eluting with 20-30% EtOAc/hexanes to give 15D.

Step 5. To a reaction mixture of 14D (1.0 equiv.), copper(I) iodide(0.05 equiv.), 8-hydroxyquinoline (0.1 equiv.), and potassium phosphatetribasic (2.0 equiv.) in DMF (0.2 M) under nitrogen atmosphere is added15D (1.2 equiv.) and the reaction mixture is heated at 120° C. for 24 h.The reaction mixture is cooled to room temperature and then diluted withEtOAc. The mixture is filtered through a pad of diatomaceous earth andthe filtrated is evaporated under vacuum. The crude residue is purifiedon a silica gel column eluting with EtOAC/Heaxanes to give 15E.

Step 6. A 0° C. suspension of 15E (1.0 equiv.) in 1,4-dioxane (0.062 M)and water (1/3 of THF) is treated with sulfamic acid (6.0 equiv.). Asolution of sodium chlorite (1.3 equiv.) and potassium dihydrogenphosphate (12 equiv.) in water (1.2 M) is added via dropping funnel over20 min. After the addition is complete, the ice bath is removed and thereaction mixture is stirred at room temperature for 3 h. THF is added,and the reaction mixture is stirred at room temperature for anadditional 3 h. The reaction mixture is diluted with water and extractedwith EtOAc (2×). The combined organic layers are washed with water andbrine and then dried over Na₂SO₄, filtered, and concentrated. Theresidue is triturated with ethyl acetate/hexanes to afford 15F.

Step 7. To a solution of compound 15F (1 equiv.) in CH₂Cl₂ (0.2 M) isadded 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until allof 15F is converted to 15G. After concentration, the residue is purifiedin a reverse phase preparative HPLC to provide 15G.

Step 8. A solution of compound 15G (1 equiv.) and DIPEA (10 equiv.) inDMF (0.2 M) is added drop-wise to a solution of HATU (1.4 equiv.) in DMF(0.1 M) at 0° C. After complete addition, the mixture is stirred at 0°C. for a further 30 min. Water is added and the mixture is extractedwith EtOAc three times. The combined organics are washed with saturatedNaHCO₃ twice, brine, dried over Na₂SO₄, and evaporated. The residue ispurified with a silica gel column eluted with EtOAc/Hexanes to provide15.

Examples 18 and 18-1

Examples 18 and 18-1 may be prepared according to the following schemeusing racemic or enantiomerically enriched starting materials:

Step 1. To a reaction mixture of 14D (1.0 equiv.), 18A (1.2 equiv.), andcopper(I) iodide (0.05 equiv.) in DMF (0.2 M) under nitrogen atmosphereis added NaH (3.0 equiv.). The reaction mixture is heated at 120° C. for24 h, and then is cooled to room temperature and diluted with EtOAc. Themixture is filtered through a pad of diatomaceous earth and thefiltrated is evaporated under vacuum. The crude residue is purified on asilica gel column eluting with EtOAc/Heaxanes to give 18B.

Step 2. To a reaction mixture of 18B (1.0 equiv.) in DMF (0.2 M) areadded KOH (2 equiv.) and I₂ (1.1 equiv.). The reaction mixture isstirred at room temperature for 1 h, and then quenched with NaHSO₃ andextracted with EtOAc. The combined organics are washed with saturatedNaHCO₃ twice, brine, dried over Na₂SO₄, and evaporated. The residue ispurified with a silica gel column eluted with EtOAc/Hexanes to provide18C.

Step 3. To a solution of compound 18C (1 equiv.) in CH₂Cl₂ (0.2 M) isadded 4 M HO/dioxane (10 equiv.) and the mixture is stirred until all of18C is converted to 18D. After concentration, the residue is purified ina reverse phase preparative HPLC to provide 18D.

Step 4. To a solution of 18D (1 equiv.) and DIPEA (2 equiv.) in toluene(0.01 M) is added Pd(P-t-Bu₃)₂ (1 equiv.). The reaction mixture isheated at 100° C. under 4 bar CO overnight, and then concentrated. Theresidue is purified on a silica gel column eluting with EtOAc/hexanes toprovide 18.

Example 20

Example 20 was prepared according to the following scheme:

Step 1. tert-Butyl (2-(4-fluoro-2-formylphenoxy)ethyl)carbamate (20C). Asolution of aldehyde 20A (1.5 g, 11 mmol), chloride 20B (2.1 g, 12mmol), potassium carbonate (7.4 g, 54 mmol) and potassium iodide (36 mg,0.2 mmol) in DMF (11 mL) were heated to 60° C. and stirred for 15 hours.Additional chloride 20B (1.0 g, 6 mmol) and further heating at 80° C.for 5 hours completed the reaction. The mixture was cooled to roomtemperature and diluted by addition of water (250 mL). The mixture wasextracted with ethyl acetate (3×300 mL) and the combined extracts werewashed with water (200 mL) and brine (100 mL), dried with sodiumsulfate, and concentrated under reduced pressure. Flash chromatography(ISCO system, silica, 0-20% ethyl acetate in hexane) provided 20C (3.0g, 99%) as a viscous oil. LRESIMS m/z 306.1 [M+Na]⁺, calcd. forC₁₄H₁₈F₁N₁Na₁O₄ 306.1.

Step 2. tert-Butyl(2-(4-fluoro-2-((methylamino)methyl)phenoxy)ethyl)carbamate (20D).Aldehyde 20C (2.5 g, 8.8 mmol) and methylamine (0.69 g, 22 mmol) inmethanol (88 mL) were heated to 60° C. and stirred for 1 hour. Themixture was cooled to room temperature and sodium borohydride (0.33 g,8.8 mmol) was added. The mixture was stirred for 30 minutes thenquenched by addition of water (200 mL). The mixture was extracted withdichloromethane (4×100 mL) and the combined extracts dried with brine(50 mL), sodium sulfate and concentrated under reduced pressure. Flashchromatography (ISCO system, silica, 0-100% of (10% methanol in ethylacetate) in hexane) provided the title compound (2.1 g, 80%) as a gel.LRESIMS m/z 299.2 [M+H]⁺, calcd. for C₁₅H₂₄F₁N₂O₃ 299.2.

Step 3. Ethyl5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(20F). Amine 20D (2.1 g, 7.0 mmol), ester 20E (1.59 g, 7.0 mmol) andHünig's base (7.0 mL, 5.2 g, 40 mmol) in butanol (17 mL) were heated at110° C. for 25 minutes. The reaction was cooled and diluted with water(250 mL). The mixture was extracted with dichloromethane (4×100 mL) andthe combined extracts dried with sodium sulfate. The mixture wasconcentrated under reduced pressure. F lash chromatography (ISCO system,silica, 20-100% ethyl acetate in hexane) provided the title compound(2.1 g, 75%) as a solid. LRESIMS m/z 488.3 [M+H]⁺, calcd. forC₂₄H₃₁F₁N₅O₅ 488.2.

Step 4.5-((2-(2-((tert-Butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (20G). Sodium hydroxide (40 mL, 2 M in water) was added to astirred solution of ester 20F (2.1 g, 4.3 mmol) intetrahydrofuran:methanol (3:2, 100 mL) at room temperature. The reactionwas heated to 60° C. and stirred for 6.5 hours. The mixture was cooledto 0° C. and acidified with hydrochloric acid (45 mL, 2 M in water) thendiluted with water (100 mL). The mixture was extracted with ethylacetate (4×150 mL) and the combined extracts dried with brine (50 mL)and sodium sulfate. The mixture was concentrated under reduced pressureto provide the title compound (1.92 g, 97%) as a solid. LRESIMS m/z460.2 [M+H]⁺, calcd. for C₂₂H₂₇F₁N₅O₅ 460.2.

Step 5.5-((2-(2-Aminoethoxy)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (20H). Hydrochloric acid (5 mL, 4M in dioxane) was added to astirred solution of carboxylic acid 20G (1.92 g, 4.2 mmol) indichloromethane (25 mL) at room temperature. The reaction was stirredfor 2 hours then concentrated under reduced pressure to provided thetitle compound as a solid. LRESIMS m/z 360.2 [M+H]⁺, calcd. forC₁₇H₁₀F₁N₅O₃ 360.2.

Step 6. Under an atmosphere of argon HATU (1.67 g, 4.4 mmol) was addedto a stirred solution of carboxylic acid 20H (1.50 g, 4.2 mmol) andHünig's base (7.28 mL, 5.40 g, 41.8 mmol) in DMF:dichloromethane (5:1,60 mL) at −78° C. The reaction was slowly warmed to room temperature andstirred for 3 hours then quenched water (300 mL). The mixture wasextracted with ethyl acetate (3×100 mL) then dichloromethane (2×100 mL)and the combined extracts dried with brine (50 mL) and sodium sulfate.The mixture was concentrated under reduced pressure. Flashchromatography (ISCO system, silica, 1-4% methanol in dichloromethane)followed by recrystallization from ethyl acetate/methanol providedExample 20 (0.98 g, 68%, 2 steps) as a solid. LRESIMS m/z 342.2 [M+H]⁺,calcd. for C₁₇H₁₇F₁N₅O₂ 342.1; ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (dd,J=6.9, 2.7 Hz, 1H), 8.76 (d, J=7.9 Hz, 1H), 8.10 (s, 1H), 7.19-7.25 (m,1H), 7.03-7.07 (m, 2H), 6.72 (d, J=7.9 Hz, 1H), 5.64 (dd, J=14.9, 1.5Hz, 1H), 4.48 (dt, J=10.2, 4.3 Hz, 1H), 4.04-4.10 (m, 2H), 3.81-3.87 (m,1H), 3.58 (s, 3H), 3.38-3.46 (m, 1H).

Alternative Synthesis of Example 20:

Example 20 was also prepared by the following alternative route:

Step 1. Ethyl 5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (20J). Toa mixture of 201 (150.00 g, 1.08 mmol) and ethyl(E)-3-ethoxyprop-2-enoate (292.16 g, 2.03 mol) in DMF (3.2 L) was addedCs₂CO₃ (656.77 g, 2.02 mol) in one portion at 20° C. under N₂. Themixture was stirred at 110° C. for 6 hours. The mixture was cooled to20° C. and filtered through a pad of diatomaceous earth. The filter cakewas washed with ethyl acetate (3×30 mL). The filtrate was added to H₂O(2 L) and acidified with HOAc to pH=4. The resultant precipitate wasfiltered to afford 20J (173.00 g, 834.98 mmol, 86.36% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=7.91 Hz, 1H), 8.12 (s,1H), 6.13 (d, J=7.91 Hz, 1H), 4.27 (q, J=7.11 Hz, 2H), 1.28 (t, J=7.09Hz, 3H).

Step 2. 5-Chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (20K). To amixture of 20J (158.00 g, 762.59 mmol) in MeCN (1.6 L) was added POCl₃(584.64 g, 3.81 mol) at 20° C. under N₂. The mixture was stirred at 100°C. for 2 hours. The mixture was cooled to 20° C. and poured intoice-water (5000 mL) in portions at 0° C. and stirred for 20 min. Theprecipitate was filtered and dried to afford 20K (110.00 g, 487.52 mmol,63.93% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (d,J=7.28 Hz, 1H), 8.66 (s, 1H), 7.41 (d, J=7.15 Hz, 1H), 4.31 (q, J=7.15Hz, 2H), 1.32 (t, J=7.09 Hz, 3H).

Step 3. 4-Fluoro-2-methylaminomethyl-phenol (20M). To a solution of 20 L(5.00 g, 35.69 mmol, 1.00 eq.) in MeOH (50.00 mL) was added aqueousmethanamine (8.8 mL, 71.38 mmol, 25%, 2.00 eq) in one portion at 25° C.under N₂. The mixture was stirred at 25° C. for 3 hours, then NaBH₄(2.70 g, 71.38 mmol, 2.00 eq) was added portion-wise. And the mixturewas stirred at 25° C. for another 9 hours. TLC showed the reaction wascompleted. The mixture was concentrated in reduced pressure at 45° C.The residue was poured into water (50 mL). The aqueous phase wasextracted with dichloromethane (3×200 mL) and the combined organic phasewas washed with brine (200 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuum to afford 20M (5.10 g, 32.87 mmol, 92.09%yield) as a colourless solid. ¹H NMR (400 MHz, CDCl₃) δ 6.86 (dt, J=3.0,8.7 Hz, 1H), 6.78-6.69 (m, 2H), 3.93 (s, 2H), 2.48 (s, 3H).

Step 4.5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid ethyl ester (A1). To a suspension of 20M (33.70 g, 217.17 mmol,1.00 eq.) and 20K (49.00 g, 217.17 mmol, 1.00 eq.) in n-BuOH (740.00mL), DIPEA (159.98 g, 1.24 mol, 5.70 eq.) was added. The reactionmixture was stirred at 120° C. for 2 hours under nitrogen. TLC showedreaction completion. The solution was cooled to 25° C., and then removedthe solvent. The residue was diluted with water (500 mL) and extractedwith dichloromethane (3×500 mL). The combined organic extracts waswashed with brine (300 mL), dried over anhydrous Na₂SO₄ and concentratedunder vacuum. The residue was triturated by EtOAc (100 mL) to give A1(60.00 g, 174.25 mmol, 80.24% yield) as a white solid. ¹H NMR (500 MHz,Chloroform-d) δ 9.71 (s, 1H), 8.32 (d, J=7.9 Hz, 1H), 8.30 (s, 1H),6.98-6.87 (m, 3H), 6.37 (d, J=7.9 Hz, 1H), 4.82 (s, 2H), 4.42 (q, J=7.1Hz, 2H), 3.21 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).

Step 5.5-{[2-(2-tert-Butoxycarbonylamino-ethoxy)-5-fluoro-benzyl]-methyl-amino}-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid ethyl ester (B1). To a solution of A1 (102.85 g, 298.6 mmol, 1eq.), (2-chloro-ethyl)-carbamic acid tert-butyl ester (56.33 g, 313.5mmol, 1.05 eq.) in DMF (854 mL) were added K₂CO₃ (206.41 g, 1493 mmol,5.0 eq.). The mixture was heated at 80° C. for 20 hours with ˜85%conversion of the starting material to the product by LC-MS. Additionalportions of (2-chloro-ethyl)-carbamic acid tert-butyl ester (5.633 g,31.35 mmol, 0.1 eq.) and K₂CO₃ (41.282 g, 298.6 mmol, 1 eq.) were addedto the reaction flask. The reaction was continued at 80° C. for anadditional 21 hours. The mixture was then cooled to room temperature,quenched with water (1000 ml) and extracted with EtOAc (3×900 mL). Thecombined organic extracts were then washed with water (3×700 mL) andbrine (500 mL), dried over Na₂SO₄, and concentrated. The resultingresidue was purified by a silica gel column eluting with EtOAc/Hexane(0-70% to afford B1 as a white solid (128.74 g, 96.7% yield). LC-MS(ESI) m/z 510.1 (M+Na)⁺; ¹H NMR (500 MHz, Chloroform-d) δ 8.30 (s, 1H),8.26 (s, 1H), 6.92 (td, J=8.6, 3.3 Hz, 1H), 6.83-6.76 (m, 1H), 6.31 (s,1H), 4.93 (s, 2H), 4.51-4.44 (m, 1H), 4.36 (q, J=7.2 Hz, 2H), 4.03 (t,J=4.9 Hz, 2H), 3.69-3.63 (m, 1H), 3.51 (s, 2H), 3.30 (s, 2H), 1.44 (s,9H), 1.41-1.35 (t, J=7.2 Hz, 3H).

Step 6.11-Fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(20). To a solution of B1 (128.74 g, 264.07 mmol, 1 eq.) in methanol(750 mL) and THF (250 mL) was added LiOH H₂O (55.40 g, 1320 mmol, 5.0eq.) in H₂O (250 mL). The clear solution was heated at 70° C. for 2hours. The reaction was neutralized at 0° C. with aq. HCl (2M, 250 mL)to pH<5, and then extracted with CH₂Cl₂ (1×1000 mL, 3×500 mL). Thecombined organics were washed with brine (300 mL), and dried overNa₂SO₄. After filtration, evaporation, and high vacuum dry, a whitesolid was obtained (126.47 g, 275.25 mmol, 104% yield). To a solution ofthe acid (121.30 g, 264 mmol) in CH₂Cl₂ (996 mL) was added HCl indioxane (4 M, 204 mL) at 0° C. Keep stirring from 0° C. to roomtemperature for 27 hours until the de-Boc was complete by LC-MS. Thewhite solid was filtered, washed with DCM (400 mL), and high vacuumdried to provide a white solid of the amine 3HCl salt (123.55 gram)which was used directly without further purification. To a solution ofDIPEA (169.4 g, 228 mL, 1310 mmole) in DMF (3.7 L) and CH₂Cl₂ (1.0 L)was added the acid amine HCl salt (22.92 g, 49.0 mmol, 1.00 eq.). Afterthe solid salt was dissolved completely, pentafluorophenyldiphenylphosphinate (FDPP) in CH₂Cl₂ (1.1 M, 19.76 g, 51.44 mmol, 1.05eq.) was added. The coupling was complete in 30 minutes by LC-MS, andthen the second portions of the salt and FDPP was added following thesame procedure as the first portion. The addition of the salt followedby FDPP was repeated every 30 minutes and monitored by LC-MS for everycycle of the addition. A total of the salt (123.55 g, 264 mmol, 1.00 eq)and FDPP (106.44 g, 277 mmol, 1.05 eq.) were added to the reaction flaskin portion. The reaction solution was concentrated to a volume of 500 mLand a lot of precipitate was formed. The solid product 20 was filteredand washed with DMF (50 mL×3). The filtrate was poured into water (2 L)and additional product was precipitated out. The solid product wasfiltered and washed with water (100 mL×3). The combined solid productwas dried, and re-dissolved in 10% methanol in dichloromethane (1.5 L)and then ethyl acetate was added (1 L). The solution was condensed to500 mL and a lot of white solid was formed. After filtration and highvacuum dry, a white solid compound 20 was obtained (74.58 g, 83% yield).

Powder X-Ray Diffraction (PXRD) of Example 20.

A sample of Example 20, crystalline polymorph form 1, was transferred toa zero background plate for PXRD analysis. The PXRD data was obtainedusing a Bruker D8 X-ray diffractometer according to manufacturerrecommended procedures. Parameters for scan: 2-theta range: 4.5 to 39.1degrees; step size: 0.02 degrees; step time: 1 second; analysis time:180 seconds.

Diffraction peaks are typically measured with an error of ±0.1 degrees(2θ).

Results are shown in FIG. 1. The data is summarized in Table 1.

TABLE 1 2-θ (degrees) d-value Peak Intensity (Counts) Peak Intensity (%)10.68 9.611 31.15 5.2 11.96 8.586 19.11 2.9 15.26 6.737 20.92 4.4 19.645.244 27.57 6.4 21.94 4.701 452.41 100 23.96 4.309 91.85 18.2 26.823.857 10.92 2.2

Differential Scanning Calorimetry (DSC) of Example 20.

DSC measurements, shown in FIG. 2, were carried out using a Seiko ModelSSC/5200 Differential Scanning Calorimeter, A 7.92 mg sample of Example20, crystalline polymorph form 1, was quilibrated at 36° C., and thenramped to 380° C. at a rate of 10° C./min. The sample of Example 20,crystalline polymorph form 1, showed a melting point of 298.9° C.

Example 26

Example 26 may be prepared according to the following scheme:

Step 1. Titanium(IV) isopropoxide (1.3 equiv.) is added to acommercially available solution of methylamine in methanol (2 M, 3equiv.) followed by the addition of the starting aldehyde 14C (1.0equiv.). The reaction mixture is stirred at ambient temperature for 5 h,after which sodium borohydride (1.0 equiv.) is added and the resultingmixture is further stirred for another period of 2 h. The reaction isthen quenched by the addition of water, the resulting inorganicprecipitate is filtered and washed with EtOAc. The organic layer isseparated and the aqueous part is further extracted with EtOAc (×2). Thecombined extracts are dried (K₂CO₃) and concentrated in vacuo to give26A.

Step 2. A mixture of compound 26A (1 equiv.) and DIPEA (2 equiv.) inn-BuOH (0.2 M) is heated at 120° C. overnight, cooled to ambienttemperature, and then concentrated. The residue is purified with asilica gel column eluting with EtOAc/Hexanes to provide the product 26B.

Step 3. To a solution of compound 26B (1 equiv.) in CH₂Cl₂ (0.2 M) isadded 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until allof 26B is converted to 26C. After concentration, the residue is purifiedin a reverse phase preparative HPLC to provide 26C.

Step 4. To a solution of 26C (1 equiv.) and DIPEA (2 equiv.) in toluene(0.01 M) is added Pd(P-t-Bu₃)₂ (1 equiv.). The reaction mixture isheated at 100° C. under 4 bar CO overnight, and then concentrated. Theresidue is purified on a silica gel column eluting with EtOAc/hexanes toprovide 26.

Examples 37 and 37-1

Examples 37 and 37-1 may be prepared according to the following schemefrom racemic or enantiomerically enriched starting materials:

Step 1. Compound 37B is prepared from compound 2C and compound 37A usingthe method described for Example 2, Synthesis A, Step 2.

Step 2. Compound 37C is prepared from compound 37B using the methoddescribed in Example 2, Synthesis A, Step 3.

Step 3. Example 37 is prepared from compound 37C using the methoddescribed in Example 2, Synthesis A, Step 4.

Examples 38 and 38-1

Examples 38 and 38-1 may be prepared according to the following schemefrom racemic or enantiomerically enriched starting materials:

Step 1. Compound 38B is prepared from compounds 2C and 38A as describedin Example 2, Synthesis A, Step 2.

Step 2. Compound 38C is prepared from compound 38B using the methoddescribed in Example 2, Synthesis A, Step 3.

Step 3. Example 38 is prepared from compound 38C using the methoddescribed in Example 2, Synthesis B, Step 4.

Example 39

Example 39 was prepared according to the following schemes:

Step 1. 2-(3-Chloro-4-fluoro-2-formyl-phenoxy)-ethyl]-carbamic acidtert-butyl ester (39B). To a solution of2-chloro-3-fluoro-6-hydroxy-benzaldehyde (39A, 53 mg, 0.3 mmol) and(2-chloro-ethyl)-carbamic acid tert-butyl ester (135 mg, 0.75 mmol) inDMF (5 mL) were added KI (2.0 mg, 0.012 mmol) and K₂CO₃ (105 mg, 0.75mmol). The mixture was microwaved at 100° C. for 2 h. The mixture wasthen diluted with water (20 mL) and extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with water (3×20 mL) and brine (20mL), dried over Na₂SO₄ and concentrated to afford 39B. The crude residuewas used directly in the next step. LC-MS: (ESI) m/z 340.3 (M+Na)⁺.

Step 2.{[2-(3-Chloro-4-fluoro-2-methylaminomethyl-phenoxy)-ethyl]-carbamic acidtert-butyl ester (39C). To a solution of 39B (95.4 mg, 0.3 mmol) in MeOH(3 mL) was added methylamine hydrochloride (50.7 mg, 0.75 mmol). Themixture was stirred at 60° C. for 30 min. The solution was then cooledto ambient temperature and NaBH₄ (11.1 mg, 0.3 mmol) was added. Themixture was stirred at ambient temperature for 2 h. The solution wasthen diluted with water (50 mL) and extracted with DCM (3×20 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated toafford 39C. The crude residue was used directly in the next step. LC-MS:(ESI) m/z 333.3 (M+H)⁺.

Step 3.5-{[6-(2-tert-Butoxycarbonylamino-ethoxy)-2-chloro-3-fluoro-benzyl]-methyl-amino}-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid ethyl ester (39D). To a solution of 20K (67.5 mg, 0.3 mmol) and 39C(99.9 mg, 0.3 mmol) in n-BuOH (2.0 mL) was added DIEA (1.0 mL). Themixture was heated under microwave at 150° C. for 2 hours The mixturewas then diluted with water and extracted with DCM (3×20 mL). Theorganic layer was dried over Na₂SO₄, concentrated and purified by silicagel column chromatography to afford 17 as a yellow liquid. LC-MS: (ESI)m/z 522.5 (M+H)⁺.

Step 4.5-{[6-(2-tert-Butoxycarbonylamino-ethoxy)-2-chloro-3-fluoro-benzyl]-methyl-amino}-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (39E). To a solution of 39D (40 mg, 0.0776 mmol) in MeOH (1 mL) wasadded LiOH (16 mg, 0.38 mmol) and H₂O (1 mL). The mixture was stirred at60° C. for 4 h. The solution was cooled to ambient temperature,partially concentrated and acidified by aqueous HCl (1 N) until pH 2-3.The aqueous mixture was extracted with DCM (3×10 mL). The organic layerwas dried over Na₂SO₄ and concentrated to afford 39E. The crude residuewas used directly in the next step. LC-MS: (ESI) m/z 494.3 (M+H)⁺.

Step 5.5-{[6-(2-Amino-ethoxy)-2-chloro-3-fluoro-benzyl]-methyl-amino}-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (39F). To a solution of 39E (40 mg, 0.0776 mmol) in DCM (2 mL), TFA(0.4 mL) was added. The solution was stirred for 1 hr. The solvent wasremoved under rotavap. The residue was re-dissolved with DCM andre-concentrated (3×) to afford 39F as a foam-like solid. LC-MS: (ESI)m/z 393.5 (M+H)⁺.

Step 6. To a solution of 39F (36 mg, 0.078 mmol) in 10 mL of DCM wasadded DIEA (0.20 mL, 1.15 mmol). The solution was chilled with dryice/acetone bath and HATU (40.0 mg, 0.11 mmol) was added. The solutionwas allowed to warm to ambient temperature slowly. The mixture wasdiluted with water (50 mL) and extracted with EtOAc (3×50 mL). Thecombined organic layer was washed with water (3×50 mL) and brine (50mL), dried over Na₂SO₄, and concentrated. The resulting residue waspurified by a silica column (0-5% MeOH/DCM) afford Example 39 as a whitesolid (6.2 mg, 23.4%). LC-MS (ESI) m/z 376.5 (M+H)⁺. ¹H NMR (500 MHz,chloroform-d) δ 9.51 (s, 1H), 8.40-8.33 (m, 2H), 7.03 (ddd, J=8.9, 8.0,0.7 Hz, 1H), 6.78 (dd, J=9.3, 4.2 Hz, 1H), 6.40 (d, J=7.9 Hz, 1H), 5.97(dd, J=15.0, 2.1 Hz, 1H), 4.49-4.43 (m, 1H), 4.31 (ddd, J=10.9, 6.4, 4.5Hz, 1H), 4.12-4.03 (m, 1H), 3.91 (d, J=14.9 Hz, 1H), 3.72-3.63 (m, 1H),3.56 (s, 3H).

Example 40

Example 40 was prepared as shown in the following scheme:

Step 1.5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40B). To a solution of 19A (75 mg, 0.14 mmol) in MeOH (2 mL) wasadded LiOH (60 mg, 1.4 mmol) and H₂O (2 mL). The mixture was stirred at60° C. for 4 h. The solution was cooled to ambient temperature,partially concentrated and acidified by aqueous HCl (1 N) until pH 2-3.The resulting suspension was extracted with EtOAc (3×20 mL). The organiclayer was dried over Na₂SO₄ and concentrated to afford 40A. LC-MS (ESI)m/z 331.6 (M+H)⁺.

Step 2.5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-hydroxy-ethyl)-amide (40B). To a solution of 40A (140 mg, 0.42mmol) and 2-amino-ethanol (244 mg, 4 mmol) in DCM (5 mL) at 0° C. wereadded DIEA (0.20 mL, 1.15 mmol) and HATU (380.0 mg, 1.0 mmol). Thesolution was allowed to warm to ambient temperature slowly. The mixturewas then diluted with water (25 mL) and extracted with EtOAc (3×25 mL).The combined organic layers were washed with HCl (1N, 3×20 mL) and brine(50 mL), dried over Na₂SO₄ and concentrated. The resulting residue waspurified by a silica gel column eluting with 0-5% MeOH/DCM (10 CV)afford 40B as a white solid (74 mg, 47%). LC-MS (ESI) m/z 374.3 (M+H)⁺.

Step 3. To a solution of 40B (74 mg, 0.2 mmol) in THF (3 mL) and DCM (3mL) at 0° C. were added PPh₃ (131 mg, 0.5 mmol) and di-tert-butylazodicarboxylate (DTAD) (115 mg, 0.5 mmol). The mixture was allowed towarm to ambient temperature and stirred for additional 4 h. The solventwas removed and the residue was purified by a silica gel column elutingwith 0-10%, MeOH/DCM (10 CV), followed by preparative TLC to affordExample 40 as a white solid (15 mg). LC-MS (ESI) m/z 356.5 (M+H)⁺; ¹HNMR (500 MHz, chloroform-d) δ 8.12 (d, J=7.7 Hz, 1H), 6.93 (ddd, J=9.0,3.1, 0.9 Hz, 1H), 6.78 (ddd, J=9.0, 7.3, 3.0 Hz, 1H), 6.71 (dd, J=9.1,4.5 Hz, 1H), 6.28 (d, J=7.7 Hz, 1H), 5.77 (dd, J=15.2, 1.7 Hz, 1H),4.38-4.33 (m, 1H), 3.98 (s, 1H), 3.91 (d, J=1.4 Hz, 1H), 3.78 (dd,J=15.1, 0.9 Hz, 1H), 3.45 (s, 3H), 3.43-3.36 (m, 1H), 2.45 (s, 3H).

Example 41

Example 41 was prepared using the method shown in the following scheme:

Step 1. [2-(2-Acetyl-4-fluoro-phenoxy)-ethyl]-carbamic acid tert-butylester (41B). To a mixture of 1-(5-fluoro-2-hydroxy-phenyl)-ethanone(41A, 773 mg, 5.0 mmol) and (2-chloro-ethyl)-carbamic acid tert-butylester (1.80 g, 10.0 mmol) in DMF (20 mL) were added KI (2.0 mg, 0.012mmol) and Cs₂CO₃ (3.26 g, 10.0 mmol). The mixture was stirred at 80° C.overnight. The mixture was then cooled to ambient temperature, dilutedwith EtOAc, and washed with 1 N NaOH (5×10 mL) until LCMS showed no1-(5-fluoro-2-hydroxy-phenyl)-ethanone peak. The organic layer was driedover Na₂SO₄ and concentrated. The residue was then purified by a silicagel column eluting with EtOAc/hexane (0-30%, 10 CV) to afford thedesired product 41B as a yellow solid (1.1 g, 73.8%). LC-MS (ESI) m/z320.3 (M+Na)⁺.

Step 2. tert-Butyl(2-(4-fluoro-2-(1-hydroxyethyl)phenoxy)ethyl)carbamate (41C). To asolution of 41B (1.0 g, 3.36 mmol) in MeOH (10 mL) was added NaBH₄ (640mg, 16.8 mmol) in portions. The mixture was stirred at ambienttemperature for 2 h. The solution was then diluted with water (50 mL)and extracted with DCM (3×20 mL). The combined DCM layers were driedover Na₂SO₄ and concentrated. The residue was purified by a silica gelcolumn eluting with EtOAc/hexane (0-50%, 10 CV) to afford the desiredproduct as a pale yellow solid (0.75 g, 75%). LC-MS (ESI) m/z 322.3(M+Na)⁺; ¹H NMR (500 MHz, chloroform-d) δ 7.11 (dd, J=9.2, 3.4 Hz, 1H),6.89 (ddd, J=9.0, 7.9, 3.2 Hz, 1H), 6.77 (dd, J=8.9, 4.4 Hz, 1H), 5.09(q, J=6.6 Hz, 1H), 4.92 (d, J=4.4 Hz, 1H), 4.03 (t, J=5.2 Hz, 2H),3.62-3.50 (m, 2H), 1.49 (d, J=6.4 Hz, 3H), 1.45 (s, 9H).

Step 3.6-{1-[2-(2-tert-Butoxycarbonylamino-ethoxy)-5-fluoro-phenyl]-ethoxy}-imidazo[1,2-b]pyridazine-3-carboxylicacid ethyl ester (41D). To a solution of 41C (600 mg, 2.0 mmol) and{2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-ethyl}-carbamic acidtert-butyl ester (450 mg, 2.0 mmol) in dry THF (40.0 mL) at −78° C. wasadded NaH (60%, 80 mg, 2.0 mmol) in portions. The suspension was stirredat −78° C. for 4 h and allowed to warm to 0° C. and stirred foradditional 4 h. The mixture was then put in the freezer at −20° C.overnight. The mixture was then quenched with a mixture of ice and 1 NHCl and extracted with EtOAc (3×20 mL). The organic layer was dried overNa₂SO₄, concentrated and purified twice to afford the desired product asa yellow solid (240 mg, 25%). LC-MS (ESI) m/z 511.6 (M+Na)⁺; ¹H NMR (500MHz, chloroform-d) δ 8.16 (s, 1H), 7.90 (d, J=9.7 Hz, 1H), 7.16 (dd,J=9.0, 3.2 Hz, 1H), 0.95 (d, J=9.5 Hz, 1H), 6.90-6.88 (m, 1H), 6.81-6.78(m, 1H), 6.68 (q, J=6.2 Hz, 1H), 5.84-5.68 (m, 1H), 4.38 (q, J=7.2 Hz,2H), 4.15-4.09 (m, 2H), 3.60-3.52 (m, 2H), 1.65 (d, J=6.4 Hz, 3H), 1.38(d, J=7.2 Hz, 3H), 1.35 (s, 9H).

Step 4. Compound 41D was converted to Example 41 using methods analogousto those described herein. MS: 343.2 (M+H)⁺; ¹H NMR (500 MHz,Chloroform-d) δ 9.82 (d, J=7.0 Hz, 1H), 8.27 (s, 1H), 8.09 (d, J=9.5 Hz,1H), 7.18 (dd, J=8.9, 3.2 Hz, 1H), 7.01-6.94 (m, 2H), 6.83 (dd, J=9.0,4.3 Hz, 1H), 6.60-6.53 (m, 1H), 4.63-4.52 (m, 1H), 4.27-4.16 (m, 1H),4.16-4.04 (m, 1H), 3.70-3.56 (m, 1H), 1.70 (d, J=6.4 Hz, 3H)

Example 42

Example 42 was prepared using the methods shown in the following scheme:

Step 1.6-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-imidazo[1,2-b]pyridazine-3-carboxylicacid ethyl ester (42B). To a mixture of4-fluoro-2-methylaminomethyl-phenol (20 L, 305.2 mg, 1.97 mmol) and6-chloro-imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (42A,230 mg, 1.02 mmol) in DMSO (5 mL) was added KF (180 mg, 3.01 mmol). Thereaction mixture was stirred at 120° C. for 18 hours under nitrogen. Thesolution was then cooled to ambient temperature, diluted with water (20mL) and extracted with EtOAc (3×50 mL). The combined organic layers werefurther washed with water (3×50 mL) and brine (50 mL), dried over Na₂SO₄and concentrated. The residue was then purified by a silica gel columneluting with EtOAc/hexane (0-50%, 10 CV) to afford the desired productas a white solid (240 mg, 69%). LC-MS (ESI) m/z 345.2 (M+H)⁺; ¹H NMR(500 MHz, chloroform-d) δ 8.61 (s, 1H), 8.17 (s, 1H), 7.91 (d, J=10.0Hz, 1H), 7.00-6.86 (m, 4H), 4.78 (s, 2H), 4.47 (qd, J=7.2, 0.5 Hz, 2H),3.17 (s, 3H), 1.41 (td, J=7.1, 0.5 Hz, 3H).

Step 2.6-{[2-(2-tert-Butoxycarbonylamino-ethoxy)-5-fluoro-benzyl]-methyl-amino}-imidazo[1,2-b]pyridazine-3-carboxylicacid ethyl ester (42C). To a solution of6-[(5-fluoro-2-hydroxy-benzyl)-methyl-amino]-imidazo[1,2-b]pyridazine-3-carboxylicacid ethyl ester (2B, 200 mg, 0.58 mmol) and (2-chloro-ethyl)-carbamicacid tert-butyl ester (209 mg, 1.16 mmol) in DMF (5 mL) were added K₂CO₃(200 mg, 1.45 mmol) and KI (2.0 mg, 0.012 mmol). The mixture was heatedat 90° C. for 4 h under nitrogen. The mixture was then diluted withwater (20 mL) and extracted with EtOAc (3×10 mL). The combined organiclayers were then washed with water (3×5 mL) and brine (2×5 mL). Theorganic layer was dried over Na₂SO₄ and concentrated. The resultingresidue was purified by a silica gel column eluting with EtOAc/hexane(0-100%, 10 CV) to afford 42C as a white solid (203 mg, 76%). LC-MS(ESI) m/z 510.1 (M+Na)⁺; ¹H NMR (500 MHz, Chloroform-d) δ (ppm) 8.16 (s,1H), 7.85 (d, J=9.9 Hz, 1H), 7.00 (dd, J=8.9, 3.2 Hz, 1H), 6.95-6.87 (m,2H), 6.80 (dd, J=8.9, 4.3 Hz, 1H), 4.95 (s, 1H), 4.74 (s, 2H), 4.41 (q,J=7.2 Hz, 2H), 4.04 (t, J=5.2 Hz, 2H), 3.56-3.50 (m, 2H), 3.26 (s, 3H),1.43 (s, 9H), 1.40 (t, J=7.2 Hz, 3H).

Step 3. Compound 42C was converted to Example 42 using methods analogousto those described herein. MS: 342.5 (M+H)⁺; ¹H NMR (500 MHz,chloroform-d) δ 10.01 (d, J=6.9 Hz, 1H), 8.17 (s, 1H), 8.04 (d, J=10.0Hz, 1H), 7.07-7.04 (m, 1H), 7.00 (d, J=10.0 Hz, 1H), 6.96-6.92 (m, 1H),6.84 (dd, J=9.1, 4.5 Hz, 1H), 5.69 (dd, J=15.8, 1.6 Hz, 1H), 4.55 (dt,J=9.9, 3.7 Hz, 1H), 4.20-4.09 (m, 2H), 3.98 (dd, J=15.9, 1.0 Hz, 1H),3.66-3.62 (m, 1H), 3.61 (s, 3H).

Example 51-1

Step 1 To a solution of A8 (399.4 mg, 1.16 mmol) and tert-butyl(2-chloroethyl)carbamate (260.5 mg, 1.45 mmol) in DMF (5.8 mL) was addedK₂CO₃ (801.6 mg, 5.80 mmol) and heated at 80° C. with stirring for 6hours. The reaction was cooled to ambient temperature and diluted withDCM (3 mL), filtered through a syringe filter, and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),0-70% ethyl acetate in hexane) provided 51-1A (407.4 mg, 0.836 mmol, 72%yield).

Step 2. To a solution of 51-1A (407.4 mg, 0.836 mmol) in MeOH (6 mL) andTHF (4 mL) was added LiOH aqueous solution (2M, 4.0 mL) at ambienttemperature. The reaction solution was heated at 70° C. for 2 hours Thereaction flask was cooled to ambient temperature, diluted with water andmethanol, and then quenched with HCl aqueous solution (2 M, 4 mL) topH<5. The mixture was extracted with DCM (3×5 mL), dried with Na₂SO₄,concentrated under reduced, and dried on high vacuum overnight. To asolution of the acid product in DCM (6 mL) was added 4 M HCl in1,4-dioxane (2.97 mL). The mixture was stirred at room temperature for 3hours, and then concentrated under reduced pressure and dried on highvacuum. To a solution of the de-Boc product and FDPP (352.9 mg, 0.918mmol) in DMF (21 mL) was added Hunig's base (539.5 mg, 0.327 mmol) atroom temperature. The mixture was stirred for 2.5 hours, and thenquenched the reaction with 2 M Na₂CO₃ solution (21 mL). The mixture wasstirred for 15 min and then extracted with DCM (4×10 mL). The combinedextracts were dried with Na₂SO₄ and concentrated under reduced pressure.The residue was purified with flash chromatography (ISCO system, silica(12 g), 0-11.25% methanol in dichloromethane) to provide 51-1 (164.0 mg,0.480 mmol, 57.55% yield for three steps).

Example 53

Example 53 was prepared using the methods shown in the following scheme:

Step 1.5-[1-(5-Fluoro-2-hydroxy-phenyl)-ethylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (53A). To a solution5-[(5-fluoro-2-hydroxy-benzyl)-methyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid ethyl ester (20M, 300 mg, 0.87 mmol) in MeOH (5 mL), LiOH (420 mg,10 mmol) was added, followed by 5 mL of H₂O. The mixture was allowed tostir at 60° C. for 4 h. The solution was cooled to ambient temperature,partially concentrated and acidified with 1 N HCl until pH 2-3. Theresulting suspension was extracted with EtOAc (3×20 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue wasused directly in the next step. LCMS (ESI⁺) m/z 317.4 (M+H)⁺.

Step 2.3-({5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carbonyl}-amino)-2-hydroxy-propionicacid methyl ester (53B). To a solution of 53A (80 mg, 0.25 mmol) and3-amino-2-hydroxy-propionic acid methyl ester hydrochloride (70 mg, 0.5mmol) in DCM (5 mL) at 0° C. was added DIPEA (1.0 mL, 5.7 mmol),followed by HATU (140.0 mg, 0.5 mmol). The solution was allowed to warmto ambient temperature slowly. The mixture was diluted with water (25mL) and extracted with EtOAc (3×25 mL). The combined organic layers werewashed with 1 N HCl (3×20 mL) and brine (50 mL), and dried over Na₂SO₄.The solvent was removed and the resulting white solid was used directlyin the next step. LC-MS (ESI⁺) m/z 418.4 (M+H)⁺.

Step 3. Methyl11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxylate(53C). To a solution of 53B (83 mg, 0.2 mmol) in DCM (5 mL) was addedPPh₃ (263 mg, 1.0 mmol), followed by CBr₄ (332 mg, 1.0 mmol). Themixture was stirred at ambient temperature overnight. The solvent wasremoved and the residue was re-dissolved in DMF (5 mL), followed by theaddition of K₂CO₃ (116.8 mg, 0.84 mmol). The mixture was then stirred at80° C. until a complete formation of the desired product. The mixturewas then diluted with EtOAc and washed with water. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified by silicacolumn (0-10%, MeOH/DCM) to afford 53C as a white solid (40 mg). LC-MS(ESI⁺) m/z 400.2 (M+H)⁺.

Step 4. To 53C (20 mg, 0.05 mmol) was added NH₃ in MeOH solution (7 N, 2mL). The mixture was stirred at 60° C. overnight. The solvent wasremoved and the residue was purified by silica column (0-10%, MeOH/DCM)to afford Example 53 as an off-white solid (8 mg). LC-MS (ESI⁺) m/z385.5 (M+H)⁺; ¹H NMR (300 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.34 (d,J=7.9 Hz, 1H), 8.17 (s, 1H), 6.99-6.92 (m, 2H), 6.77 (dd, J=6.2, 3.5 Hz,1H), 6.38 (d, J=7.9 Hz, 1H), 5.63-5.44 (m, 2H), 5.09 (dd, J=11.0, 8.4Hz, 1H), 4.38 (dd, J=14.7, 11.0 Hz, 1H), 4.28-4.17 (m, 1H), 4.17-4.07(m, 2H), 3.22 (s, 3H).

Example 54

Example 54 was prepared using the method shown in the following scheme:

To a solution of Compound 53C (20 mg, 0.05 mmol) in MeOH (2 mL) wasadded NaBH₄ (19 mg, 0.5 mmol) portion wise. The mixture was stirred for4 h. The solvent was removed and the residue was purified by silicacolumn (0-10%, MeOH/DCM) to afford the desired product as a white solid(8 mg). LC-MS (ESI⁺) m/z 372.5 (M+H)⁺; ¹H NMR (300 MHz, Chloroform-d) δ8.39 (s, 1H), 8.32 (d, J=7.9 Hz, 1H), 7.01-6.85 (m, 3H), 6.35 (d, J=8.0Hz, 1H), 5.55-5.43 (m, 1H), 4.92-4.82 (m, 1H), 4.09-3.98 (m, 2H),3.80-3.70 (m, 3H), 3.23 (s, 3H).

Example 93

Step 1. To a solution of tert-butyl (R)-(2-hydroxypropyl)carbamate (1.00g, 5.71 mmol) and tosyl chloride (1.14 g, 6.00 mmol) in DCM (29 mL) wasadded triethylamine (1.44 g, 14.28 mmol and the mixture was stirred atroom temp for 48 hour. The reaction solution was concentrated underreduced pressure and the residue was purified with flash chromatography(ISCO system, silica (40 g), 0-20% ethyl acetate in hexane) to provide(R)-1-((tert-butoxycarbonyl)amino)propan-2-yl 4-methylbenzenesulfonate(1.12 g, 3.40 mmol, 59.54% yield).

Step 2. To a solution of A8 (100.00 mg, 0.290 mmol) and(R)-1-((tert-butoxycarbonyl)amino)propan-2-yl 4-methylbenzenesulfonate(143.50 mg, 0.436 mmol) in DMF (1.45 mL) was added K₂CO₃ (200.7 mg, 1.45mmol) and heated at 80° C. with stirring for 16 hour. The reaction wascooled to ambient temperature and diluted with DCM (3 mL), filteredthrough a syringe filter, and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 0-60% ethyl acetate inhexane) provided 93A (32.90 mg, 0.0656 mmol, 22.59% yield).

Step 3. To a solution of 93A (32.90 mg, 0.0656 mmol) in MeOH (3 mL) andTHF (2 mL) was added LiOH aqueous solution (2M, 2 mL) at ambienttemperature. The reaction solution was heated at 70° C. for 2 hours Thereaction flask was cooled to ambient temperature, diluted with water andmethanol, and then quenched with HCl aqueous solution (2 M, 2 mL) topH<5. The mixture was extracted with DCM (3×5 mL), dried with Na₂SO₄,concentrated under reduced and dried on high vacuum overnight. To asolution of the acid product in DCM (4 mL) was added 4 M HCl in1,4-dioxane (2.0 mL). The mixture was stirred at room temperature for 3hours, and then concentrated under reduced pressure and dried on highvacuum. To a solution of the de-Boc product and FDPP (27.62 mg, 0.0719mmol) in DMF (1.6 mL) was added Hunig's base (42.23 mg, 0.327 mmol) atroom temperature. The mixture was stirred for 2.5 hours, and thenquenched the reaction with 2 M Na₂CO₃ solution (2 mL). The mixture wasstirred for 15 min then extracted with DCM (4×10 mL). The combinedextracts were dried with Na₂SO₄ and concentrated under reduced pressure.The residue was purified with flash chromatography (ISCO system, silica(12 g), 0-10% methanol in dichloromethane) to provide 93 (10.1 mg,0.0284 mmol, 43.49% yield for three steps).

Examples 104, 106 and 107

Step 1. To a solution of A17 HCl (38 mg, 0.096 mmol) and tert-butyl(2-chloroethyl)carbamate (12.9 mg, 0.072 mmol) in DMF (0.5 mL) was addedK₂CO₃ (33.1 mg, 0.24 mmol) and heated at 80° C. with stirring for 1.5hour. The reaction was cooled to ambient temperature and diluted withDCM (3 mL), filtered through a syringe filter, and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),0-60% ethyl acetate in hexane) provided 104A (20.8 mg, 0.0413 mmol,86.3% yield).

Step 2. 104 was prepared according to General Method C from 104A as awhite solid.

Step 3. To a solution of 104 (4.6 mg, 0.0129 mmol) in DCM (0.3 mL) wasadded methyl 3-chlorobenzoperoxoate (2.2 mg, 0.0129 mmol) and thereaction was stirred for 20 minutes followed by addition of saturatedNaHCO₃ solution (3 mL) and extraction with DCM (4×4 mL). The combinedextracts were dried with Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (ISCO system, silica (12 g), 0-12.5% methanol indichloromethane) provided 106 (0.5 mg, 10.4% yield) and 107 (1.7 mg,33.9% yield).

The following examples were prepared using methods analogous to thosedescribed herein especially General Methods A, B and C as describedherein.

Ex. Analytical Data 11-1 MS: 377.7 (M + H)⁺; ¹H NMR (500 MHz,chloroform-d) δ 8.49 (d, J = 7.9 Hz, 1H), 8.29 (s, 1H), 7.13 (dd, J =9.2, 7.8 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.92 (dd, J = 9.4, 3.9 Hz,1H), 6.82 (d, J = 7.7 Hz, 1H), 4.63-4.55 (m, 1H), 4.45 (dd, J = 10.8,5.4 Hz, 1H), 4.31-4.23 (m, 1H), 4.00 (dd, J = 16.2, 8.7 Hz, 1H), 1.70(d, J = 6.9 Hz, 3H). 20 MS: 342.2 [M + H]⁺. ¹H NMR (500 MHz, DMSO-d₆)9.43 (dd, J = 6.9, 2.7 Hz, 1 H), 8.76 (d, J = 7.9 Hz, 1 H), 8.10 (s, 1H), 7.19-7.25 (m, 1 H), 7.03-7.07 (m, 2 H), 6.72 (d, J = 7.9 Hz, 1 H),5.64 (dd, J = 14.9, 1.5 Hz, 1 H), 4.48 (dt, J = 10.2, 4.3 Hz, 1 H),4.04-4.10 (m, 2 H), 3.81-3.87 (m, 1 H), 3.58 (s, 3 H), 3.38-3.46 (m, 1H). 39 LC-MS (ESI) m/z 376.5 (M + H)⁺. ¹H NMR (500 MHz, chloroform-d) δ9.51 (s, 1H), 8.40-8.33 (m, 2H), 7.03 (ddd, J = 8.9, 8.0, 0.7 Hz, 1H),6.78 (dd, J = 9.3, 4.2 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 5.97 (dd, J =15.0, 2.1 Hz, 1H), 4.49- 4.43(m, 1H), 4.31 (ddd, J = 10.9, 6.4, 4.5 Hz,1H), 4.12-4.03 (m, 1H), 3.91 (d, J = 14.9 Hz, 1H), 3.72-3.63 (m, 1H),3.56 (s, 3H). 40 MS: 356.5 (M + H)⁺; ¹H NMR (500 MHz, chloroform-d) δ8.12 (d, J = 7.7 Hz, 1H), 6.93 (ddd, J = 9.0, 3.1, 0.9 Hz, 1H), 6.78(ddd, J = 9.0, 7.3, 3.0 Hz, 1H), 6.71 (dd, J = 9.1, 4.5 Hz, 1H), 6.28(d, J = 7.7 Hz, 1H), 5.77 (dd, J = 15.2, 1.7 Hz, 1H), 4.38-4.33 (m, 1H),3.98 (s, 1H), 3.91 (d, J = 1.4 Hz, 1H), 3.78 (dd, J = 15.1, 0.9 Hz, 1H),3.45 (s, 3H), 3.43-3.36 (m, 1H), 2.45 (s, 3H). 41 MS: 343.2 (M + H)⁺; ¹HNMR (500 MHz, Chloroform-d) δ 9.82 (d, J = 7.0 Hz, 1H), 8.27 (s, 1H),8.09 (d, J = 9.5 Hz, 1H), 7.18 (dd, J = 8.9, 3.2 Hz, 1H), 7.01- 6.94 (m,2H), 6.83 (dd, J = 9.0, 4.3 Hz, 1H), 6.60-6.53 (m, 1H), 4.63-4.52 (m,1H), 4.27-4.16 (m, 1H), 4.16-4.04 (m, 1H), 3.70-3.56 (m, 1H), 1.70 (d, J= 6.4 Hz, 3H). 42 MS: 342.5 (M + H)⁺; ¹H NMR (500 MHz, chloroform-d) δ10.01 (d, J = 6.9 Hz, 1H), 8.17 (s, 1H), 8.04 (d, J = 10.0 Hz, 1H),7.07-7.04 (m, 1H), 7.00 (d, J = 10.0 Hz, 1H), 6.96-6.92 (m, 1H), 6.84(dd, J = 9.1, 4.5 Hz, 1H), 5.69 (dd, J = 15.8, 1.6 Hz, 1H), 4.55 (dt, J= 9.9, 3.7 Hz, 1H), 4.20-4.09 (m, 2H), 3.98 (dd, J = 15.9, 1.0 Hz, 1H),3.66-3.62 (m, 1H), 3.61 (s, 3H). 43 MS: 356.6 (M + H)⁺; ¹H NMR (500 MHz,Chloroform-d) δ 8.27 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 6.96 (ddd, J =9.0, 3.1, 0.9 Hz, 1H), 6.88-6.81 (m, 1H), 6.77 (dd, J = 9.0, 4.7 Hz,1H), 6.41 (d, J = 7.9 Hz, 1H), 5.71-5.63 (m, 1H), 4.43 (dt, J = 10.0,4.4 Hz, 1H), 4.09 (ddd, J = 10.3, 8.4, 4.0 Hz, 1H), 3.96-3.92 (m, 1H),3.87 (dd, J = 15.0, 0.8 Hz, 1H), 3.77 (dd, J = 15.0, 7.2 Hz, 1H),3.55-3.51 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H). 44 MS: 370.1 (M + H)⁺; ¹HNMR (500 MHz, DMSO-d₆) 9.28 (dd, J = 5.8, 4.0 Hz, 1H), 8.71 (d, J = 7.9Hz, 1 H), 8.08 (s, 1 H), 7.16 (dd, J = 9.5, 3.0 Hz, 1 H), 6.98- 7.09 (m,2 H), 6.82 (d, J = 8.0 Hz, 1 H), 5.48 (d, J = 15.0 Hz, 1 H), 4.42-4.51(m, 1 H), 4.16-4.23 (m, 1 H), 4.04-4.14 (m, 2 H), 3.74-3.82 (m, 2 H),3.39- 3.46 (m, 1 H), 1.58-1.81 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H). 45MS: 370.1 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d₆) 8.87-8.98 (m, 1 H), 8.69-8.79 (m, 1 H), 8.04-8.12 (m, 1 H), 7.10-7.18 (m, 1 H), 6.92-7.04 (m, 3H), 5.09-5.18 (m, 1 H), 4.61-4.69 (m, 1 H), 4.50-4.56 (m, 1 H),4.41-4.49 (m, 1 H), 4.16 (d, J = 15.30 Hz, 1 H), 3.57-3.68 (m, 2 H),1.23-1.27 (m, 6 H). 46 MS: 368.1 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d₆)9.35 (dd, J = 7.0, 2.7 Hz, 1 H), 8.81 (d, J = 7.8 Hz, 1 H), 8.07-8.15(m, 1 H), 7.19 (dd, J = 9.2, 2.3 Hz, 1 H), 7.01-7.08 (m, 2 H), 6.98 (d,J = 7.8 Hz, 1 H), 5.53 (dd, J = 15.1, 1.5 Hz, 1 H), 4.47 (dt, J = 10.22,4.25 Hz, 1 H), 4.34 (t, J = 5.08 Hz, 1 H), 4.14 (d, J = 15.30 Hz, 1 H),4.02-4.10 (m, 2 H), 3.79-3.92 (m, 1 H), 1.12-1.16 (m, 1 H), 1.03- 1.08(m, 2 H), 0.81-0.86 (m, 1 H). 47 MS: 372.1 (M + H)⁺; ¹H NMR (500 MHz,DMSO-d₆) 9.25 (t, J = 4.9 Hz, 1 H), 8.71 (d, J = 7.9 Hz, 1 H), 8.07 (s,1 H), 7.22 (dd, J = 9.5, 3.0 Hz, 1 H), 7.05-7.11 (m, 1 H), 6.96-7.04 (m,1 H), 6.83 (d, J = 8.0 Hz, 1 H), 5.51 (d, J = 14.6 Hz, 1 H), 4.96 (t, J= 5.4 Hz, 1 H), 4.42-4.51 (m, 1 H), 4.24 (ddd, J = 10.9, 6.8, 4.2 Hz, 1H), 4.09-4.20 (m, 2 H), 3.91 (dt, J = 15.2, 5.5 Hz, 1 H), 3.67-3.82 (m,3 H), 3.39-3.51 (m, 1 H). 48 MS: 356.1 (M + H)⁺; ¹H NMR (500 MHz,DMSO-d₆) 9.70 (d, J = 8.6 Hz, 1 H), 8.76 (d, J = 8.0 Hz, 1 H), 8.09 (s,1 H), 7.25 (dd, J = 9.5, 3.0 Hz, 1 H), 7.01-7.11 (m, 1 H), 6.94-7.00 (m,1 H), 6.71 (d, J = 8.0 Hz, 1 H), 5.64-5.73 (m, 1 H), 4.34 (d, J = 9.6Hz, 1 H), 4.28 (t, J = 8.9 Hz, 1 H), 4.10 (d, J = 15.0 Hz, 1 H), 3.94(dd, J = 9.6, 3.6 Hz, 1 H), 3.58 (s, 3 H), 1.36 (d, J = 6.8 Hz, 3 H). 49MS: 324.1 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d₆) 9.52 (d, J = 4.5 Hz, 1 H),8.74 (d, J = 7.9 Hz, 1 H), 8.09 (s, 1 H), 7.44 (d, J = 7.6 Hz, 1 H),7.18-7.25 (m, 1 H), 7.02 (d, J = 7.9 Hz, 1 H), 6.93 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1 H), 5.69 (d, J = 14.8 Hz, 1 H), 4.47 (dt, J =10.1, 4.1 Hz, 1 H), 4.01-4.13 (m, 2 H), 3.83-3.90 (m, 1 H), 3.54-3.61(m, 3 H), 3.38-3.46 (m, 1 H). 50 MS: 328.1 (M + H)⁺; ¹H NMR (500 MHz,DMSO-d₆) 9.80 (d, J = 7.82 Hz, 1 H), 8.89 (t, J = 6.00 Hz, 1 H), 8.58(d, J = 7.62 Hz, 1 H), 8.03-8.08 (m, 1 H), 7.12- 7.18 (m, 1 H),6.99-7.05 (m, 2 H), 6.39 (d, J = 7.62 Hz, 1 H), 5.13-5.21 (m, 1 H),4.46-4.53 (m, 1 H), 3.87-4.00 (m, 4 H). 51 MS: 342.3 (M + H)⁺; ¹H NMR(500 MHz, chloroform-d with CD₃OD) δ 8.14 (s, 1H), 7.81-7.72 (m, 1H),7.10 (dd, J = 9.0, 3.0 Hz, 1H), 6.88 (ddd, J = 9.0, 7.6, 3.0 Hz, 1H),6.80 (dd, J = 9.2, 4.4 Hz, 1H), 6.20 (d, J = 7.4 Hz, 1H), 5.75 (td, J =7.2, 1.9 Hz, 1H), 4.52-4.46 (m, 1H), 4.09 (tdd, J = 9.6, 6.4, 3.9 Hz,2H), 3.60- 3.52 (m, 1H), 1.52 (d, J = 7.0 Hz, 3H). 51-1 MS: 342.2 (M +H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.71 (br d, J = 5.21 Hz, 1 H), 8.77(br d, J = 6.86 Hz, 1 H), 8.57 (d, J = 7.41 Hz, 1 H), 8.04 (s, 1 H),7.11-7.22 (m, 1 H), 6.96-7.04 (m, 2 H), 6.36 (d, J = 7.68 Hz, 1 H), 5.63(br dd, J = 6.86, 5.49 Hz, 1 H), 4.50 (dt, J = 10.15, 3.98 Hz, 1 H),4.01 (td, J = 9.61, 3.84 Hz, 1H), 3.87 (dt, J = 10.09, 3.74 Hz, 1 H),3.35-3.46 (m, 1 H), 1.45 (d, J = 7.14 Hz, 3 H). 52 MS: 376.5 (M + H)⁺;¹H NMR (500 MHz, Chloroform-d) δ 9.92 (s, 1H), 8.29- 8.18 (m, 2H), 7.01(dd, J = 9.2, 8.2 Hz, 1H), 6.77 (dd, J = 9.2, 4.2 Hz, 1H), 6.37- 6.26(m, 1H), 6.19 (d, J = 7.6 Hz, 1H), 6.12 (s, 1H), 4.53-4.45 (m, 1H), 4.14(d, J = 6.3 Hz, 1H), 4.04-3.98 (m, 1H), 3.57 (s, 1H), 1.74 (d, J = 7.3Hz, 3H). 55 MS: 385.6 (M + H)⁺; ¹H NMR (300 MHz, Methanol-d₄) 8.35 (d, J= 7.6 Hz, 1 H), 8.24 (s, 1 H), 7.24-6.96 (m, 1 H), 6.82 (m, 2 H), 6.41(dd, J = 7.7, 4.8 Hz, 1 H), 5.59 (m, 1 H), 5.31-5.05 (m, 1 H), 4.39-4.21(m, 1 H), 3.17-3.02 (m, 1 H), 1.58 (d, J = 6.9 Hz, 3H). 56 MS: 372.3(M + H)⁺; ¹H NMR (300 MHz, Methanol-d₄) δ 8.35 (d, J = 7.6 Hz, 1 H),8.18 (s, 1 H), 7.05 (d, J = 9.4 Hz, 1 H), 6.82 (dd, J = 6.5, 1.8 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1 H), 5.60 (m, 1 H), 4.92 (m, 2H), 4.08 (dd, J= 13.1, 9.9 Hz, 1 H), 3.91-3.81 (m, 2 H), 3.73 (dd, J = 12.6, 5.1 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H). 57 MS: 371.4 (M + H)⁺. ¹H NMR (300 MHz,Methanol-d₄) δ 8.46 (d, J = 7.6 Hz, 1H), 8.41 (s, 1H), 7.00 (dd, J =9.1, 2.9 Hz, 1H), 6.88-6.78 (m, 2H), 6.58 (d, J = 7.7 Hz, 1H), 5.20 (s,1H), 4.65 (s, 2H), 3.49 (q, J = 7.3 Hz, 2H). 58 MS: 358.5 (M + H)⁺. )⁺.¹H NMR (300 MHz, Chloroform-d) δ 8.37 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H),6.90 (d, J = 7.5 Hz, 3H), 6.10 (d, J = 7.6 Hz, 1H), 5.88 (s, 1H),5.11-4.85 (m, 3H), 4.20 (dd, J = 15.1, 5.7 Hz, 1H), 4.05 (dd, J = 14.0,9.9 Hz, 1H), 3.83-3.68 (m, 3H), 3.44 (d, J = 7.3 Hz, 1H). 59 MS: 386.1(M + H)⁺; ¹H NMR (500 MHz, DMSO-d₆) 9.97 (s, 1 H), 8.57 (d, J = 7.6 Hz,1 H), 8.40 (d, J = 5.9 Hz, 1 H), 8.10 (s, 1 H), 6.85 (dd, J = 8.9, 4.8Hz, 1 H), 6.60 (d, J = 7.6 Hz, 1 H), 7.23 (dd, J = 9.3, 3.2 Hz, 1 H),7.00 (td, J = 8.6, 3.2 Hz, 1 H), 5.90 (d, J = 6.4 Hz, 1 H), 4.27-4.34(m, 2 H), 3.90 (t, J = 9.33 Hz, 2 H), 3.66 (s, 3 H). 60 MS: 371.1 (M +H)⁺; ¹H NMR (500 MHz, DMSO-d₆) 9.98 (bs, 1H), 8.54 (d, J = 7.6 Hz, 1 H),8.33 (d, J = 6.24 Hz, 1 H), 8.07 (s, 1 H), 7.44 (bs, 1 H), 7.28 (bs, 1H), 7.18 (dd, J = 9.6, 3.2 Hz, 1 H), 6.94 (td, J = 8.5, 3.2 Hz, 1 H),6.83 (dd, J = 8.9, 4.9 Hz, 1 H), 6.66 (d, J = 7.5 Hz, 1 H), 5.86 (d, J =6.4 Hz, 1 H), 4.22-4.36 (m, 2 H), 3.84-3.97 (m, 2 H). 61 MS: 343.2 (M +H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.22 (dd, J = 6.87, 2.86 Hz, 1 H),8.78 (d, J = 7.45 Hz, 1 H), 8.10 (s, 1 H), 8.06 (d, J = 3.44 Hz, 1 H),7.80 (dd, J = 8.59, 2.86 Hz, 1 H), 6.74 (d, J = 8.02 Hz, 1 H), 5.44 (dd,J = 14.89, 1.72 Hz, 1 H), 4.69 (ddd, J = 10.88, 8.59, 4.58 Hz, 1 H),4.32-4.39 (m, 1 H), 4.21 (d, J = 15.47 Hz, 1 H), 3.80-3.88 (m, 1 H),3.58 (s, 3 H), 3.41-3.49 (m, 1 H). 62 MS: 371.2 (M + H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.72-8.80 (m, 2 H), 8.08 (s, 1 H), 8.01 (d, J = 2.74Hz, 1 H), 7.49 (dd, J = 8.78, 2.74 Hz, 1 H), 7.00 (d, J = 8.23 Hz, 1 H),4.94-5.06 (m, 2 H), 4.57-4.68 (m, 1 H), 4.26-4.39 (m, 2 H), 3.66-3.77(m, 1 H), 3.49-3.55 (m, 1 H), 1.56 (d, J = 6.59 Hz, 3 H), 1.22 (d, J =6.60 Hz, 3 H). 66 MS: 368.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.56 (dd, J = 6.87, 2.86 Hz, 1 H), 9.02 (d, J = 6.87 Hz, 1 H), 8.58 (d,J = 8.02 Hz, 1 H), 8.03 (s, 1 H), 7.18 (dd, J = 9.74, 2.86 Hz, 1 H),6.97-7.08 (m, 2 H), 6.41 (d, J = 7.45 Hz, 1 H), 4.68-4.80 (m, 1 H), 4.48(dt, J = 10.60, 4.15 Hz, 1 H), 4.05 (ddd, J = 10.45, 8.45, 4.01 Hz, 1H), 3.75-3.84 (m, 1 H), 3.36-3.43 (m, 1 H), 1.26-1.38 (m, 1 H). 0.63(tt, J = 8.74, 4.44 Hz, 1 H), 0.37-0.49 (m, 2 H), 0.28 (dq, J = 9.31,4.53 Hz, 1 H). 67 MS: 370.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.75 (br d, J = 6.30 Hz, 1 H), 8.78 (d, J = 7.45 Hz, 1 H), 8.57 (d, J =8.02 Hz, 1 H) 8.04 (s, 1 H), 7.06 (dt, J = 9.16, 1.43 Hz, 1 H),6.98-7.02 (m, 2 H), 6.39 (d, J = 7.45 Hz, 1 H), 5.13 (ddd, J = 10.02,7.73, 1.72 Hz, 1 H), 4.51 (dt, J = 9.88, 3.65 Hz, 1 H) 3.94 (td, J =9.88, 3.72 Hz, 1 H), 3.82-3.90 (m, 1 H), 3.39-3.43 (m, 1 H), 1.96-2.09(m, 1 H), 1.12 (d, J = 6.30 Hz, 3 H), 0.68 (d, J = 6.30 Hz, 3 H). 75 MS:356.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.73 (d, J = 8.02 Hz, 1H), 8.25 (t, J = 4.30 Hz, 1 H), 8.10 (s, 1 H), 7.14-7.21 (m, 1 H),7.00-7.04 (m, 2 H), 6.68 (d, J = 8.02 Hz, 1 H), 5.75 (br d, J = 14.32Hz, 1 H), 4.33-4.43 (m, 1 H), 4.22 (br d, J = 6.87 Hz, 1 H), 4.05 (br d,J = 14.89 Hz, 1 H), 3.59-3.68 (m, 1 H), 3.59-3.68 (m, 1 H), 3.37-3.45(m, 1 H), 1.98-2.17 (m, 2 H). 76-1 MS: 356.2 (M + H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.68 (d, J = 7.45 Hz, 1 H), 8.53 (d, J = 7.45 Hz, 1 H),8.40 (s, 1 H), 8.03 (s, 1 H), 7.11-7.18 (m, 1 H), 6.96-7.00 (m, 2 H),6.32 (d, J = 7.45 Hz, 1 H), 5.65-5.74 (m, 1 H), 4.29-4.36 (m, 1 H),4.20-4.26 (m, 1 H), 3.54-3.62 (m, 1 H), 3.39-3.47 (m, 1 H), 1.98- 2.17(m, 2 H), 1.41 (d, J = 7.45 Hz, 3 H). 84 MS: 358.2 (M + H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.78 (d, J = 6.79 Hz, 1 H), 8.58 (d, J = 7.62 Hz, 1H), 8.05 (s, 1 H), 7.36 (d, J = 2.61 Hz, 1 H), 7.21 (dd, J = 8.85, 2.68Hz, 1 H), 7.03 (d, J = 8.85 Hz, 1 H), 6.36 (d, J = 7.68 Hz, 1 H), 5.62(quin, J = 6.90 Hz, 1 H), 4.52 (dt, J = 10.15, 3.98 Hz, 1 H), 3.98-4.11(m, 1 H), 3.80-3.92 (m, 1 H), 3.35-3.47 (m, 1 H), 1.45 (d, J = 7.07 Hz,3 H). 85 MS: 356.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.73 (br d,J = 5.49 Hz, 1 H), 8.74 (d, J = 7.14 Hz, 1 H), 8.57 (d, J = 7.68 Hz, 1H), 8.04 (s, 1 H), 7.06- 7.14 (m, 1 H), 6.97-7.03 (m, 2 H), 6.37 (d, J =7.68 Hz, 1 H), 5.33-5.45 (m, 1 H), 4.51 (dt, J = 10.15, 3.43 Hz, 1 H),3.98 (td, J = 9.88, 3.84 Hz, 1 H), 3.82-3.93 (m, 1 H), 3.39 (td, J =9.61, 2.74 Hz, 1 H), 1.85-1.99 (m, 1 H), 1.62-1.76 (m, 1 H), 0.87 (t, J= 7.14 Hz, 3 H). 86 MS: 382.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.74 (dd, J = 7.16, 2.00 Hz, 1 H), 8.64 (d, J = 6.87 Hz, 1 H), 8.57 (d,J = 7.45 Hz, 1 H) 8.05 (s, 1 H), 6.95-7.06 (m, 3 H), 6.38 (d, J = 8.02Hz, 1 H), 5.47 (ddd, J = 10.60, 7.16, 1.15 Hz, 1 H), 4.54 (dt, J =10.17, 3.79 Hz, 1 H), 4.01 (td, J = 9.59, 3.72 Hz, 1 H), 3.80-3.90 (m, 1H), 3.39-3.48 (m, 1 H), 2.66-2.77 (m, 1 H), 2.12-2.23 (m, 1 H), 1.83 (brd, J = 2.29 Hz, 3 H), 1.55-1.73 (m, 2 H). 87 MS: 346.2 (M + H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 9.40 (s, 1 H), 8.77 (d, J = 8.23 Hz, 1 H), 8.10(s, 1 H), 7.19-7.26 (m, 1 H), 7.01-7.08 (m, 2 H), 6.72 (d, J = 8.23 Hz,1 H), 5.64 (dd, J = 15.09, 1.37 Hz, 1 H), 4.08 (d, J = 14.82 Hz, 1 H),3.58 (s, 3 H). 88 MS: 404.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.70 (dd, J = 6.87, 2.86 Hz, 1 H), 9.26 (d, J = 7.45 Hz, 1 H), 8.66 (d,J = 7.45 Hz, 1 H), 8.09 (s, 1 H), 7.35-7.45 (m, 4 H), 7.28-7.34 (m, 1H), 7.15 (dd, J = 9.16, 3.44 Hz, 1 H), 7.09- 7.13 (m, 1 H), 7.04-7.09(m, 1 H), 6.92 (d, J = 6.87 Hz, 1 H), 6.52 (d, J = 7.45 Hz, 1 H), 4.56(dt, J = 10.31, 4.01 Hz, 1 H), 4.08-4.14 (m, 1 H), 3.87 (ddt, J = 13.75,7.59, 3.94, 3.94 Hz, 1 H), 3.44-3.49 (m, 1 H). 89 MS: 382.2 (M + H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 9.76 (dd, J = 7.45, 2.29 Hz, 1 H), 8.77 (d,J = 7.45 Hz, 1 H), 8.58 (d, J = 8.02 Hz, 1 H), 8.05 (s, 1 H), 7.09 (dt,J = 9.74, 1.72 Hz, 1 H), 7.00 (dd, J = 6.30, 1.72 Hz, 2 H), 6.38 (d, J =7.45 Hz, 1 H), 5.56-5.63 (m, 1 H), 4.51 (dt, J = 10.17, 3.79 Hz, 1 H),3.99 (td, J = 9.59, 3.72 Hz, 1 H), 3.86 (ddt, J = 13.75, 7.45, 3.72,3.72 Hz, 1 H), 3.38-3.43 (m, 1 H), 1.94 (ddd, J = 13.89, 7.88, 6.30 Hz,1 H) 1.44 (dt, J = 14.03, 7.30 Hz, 1 H), 0.63- 0.73 (m, 1 H), 0.37-0.45(m, 1 H), 0.27-0.34 (m, 1 H), 0.18 (dq, J = 9.24, 4.75 Hz, 1 H),−0.12-−0.04 (m, 1 H). 90 MS: 372.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δppm 8.68 (d, J = 8.02 Hz, 1 H), 8.52 (d, J = 7.45 Hz, 1 H), 8.36 (t, J =4.01 Hz, 1 H), 8.04 (s, 1 H), 7.16 (dd, J = 9.45, 3.15 Hz, 1 H), 7.06(dd, J = 9.17, 4.58 Hz, 1 H), 6.95-7.02 (m, 1 H), 6.30 (d, J = 8.02 Hz,1 H), 5.66-5.75 (m, 1 H), 5.45 (d, J = 4.58 Hz, 1 H), 4.12-4.25 (m, 2H), 4.05 (d, J = 9.16 Hz, 1 H), 3.60-3.67 (m, 1 H), 3.28-3.31 (m, 1 H),1.42 (d, J = 6.87 Hz, 3 H). 91 MS: 372.2 (M + H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.70 (d, J = 6.87 Hz, 1 H), 8.53 (d, J = 7.45 Hz, 1 H),8.47 (dd, J = 8.31, 2.00 Hz, 1 H), 8.03 (s, 1 H), 7.07- 7.13 (m, 1 H),6.97-7.03 (m, 2 H), 6.34 (d, J = 7.45 Hz, 1 H), 5.60 (quind, J = 7.02,7.02, 7.02, 7.02, 1.72 Hz, 1 H), 5.36 (d, J = 4.01 Hz, 1 H), 4.42 (br d,J = 10.88 Hz, 1 H), 4.01-4.14 (m, 2 H), 3.88-3.97 (m, 1 H), 3.10-3.17(m, 1 H), 1.41 (d, J = 7.45 Hz, 3 H). 92 MS: 356.2 (M + H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ ppm 9.41 (dd, J = 6.01, 3.72 Hz, 1 H), 8.71 (d, J = 7.45Hz, 1 H), 8.58 (d, J = 7.45 Hz, 1 H), 8.06 (s, 1 H), 7.14 (dd, J = 9.74,3.44 Hz, 1 H), 7.07 (dd, J = 9.17, 4.58 Hz, 1 H), 6.96 (ddd, J = 9.17,8.02, 3.44 Hz, 1 H), 6.35 (d, J = 7.45 Hz, 1 H), 5.63-5.74 (m, 1 H),4.77- 4.89 (m, 1 H), 3.73-3.85 (m, 1 H), 3.52-3.58 (m, 1 H), 1.43 (d, J= 6.87 Hz, 3 H), 1.19 (br d, J = 6.30 Hz, 3 H). 93 MS: 356.2 (M + H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.82 (dd, J = 8.02, 2.29 Hz, 1 H), 8.81(d, J = 6.87 Hz, 1 H), 8.58 (d, J = 7.45 Hz, 1 H), 8.04 (s, 1 H), 7.12(dd, J = 9.45, 3.15 Hz, 1 H), 6.99-7.05 (m, 1 H), 6.94-6.99 (m, 1 H),6.36 (d, J = 7.45 Hz, 1 H), 5.53 (quind, J = 6.87, 6.87, 6.87, 6.87,1.15 Hz, 1 H), 4.45- 4.52 (m, 1 H), 3.90 (ddd, J = 13.46, 8.31, 4.01 Hz,1 H), 3.10-3.17 (m, 1 H), 1.46 (d, J = 6.30 Hz, 3 H), 1.44 (d, J = 7.45Hz, 3 H). 94 MS: 356.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.49(dd, J = 7.45, 2.86 Hz, 1 H), 8.77 (d, J = 7.45 Hz, 1 H), 8.09 (s, 1 H),7.15 (dd, J = 9.45, 3.15 Hz, 1 H), 7.04-7.09 (m, 1 H), 6.97-7.03 (m, 1H), 6.73 (d, J = 8.02 Hz, 1 H), 5.54 (dd, J = 14.89, 1.72 Hz, 1 H), 4.55(ddd, J = 7.59, 5.87, 4.30 Hz, 1 H), 4.08 (d, J = 14.89 Hz, 1 H),3.85-3.92 (m, 1 H), 3.59 (s, 3 H), 3.16 (ddd, J = 13.60, 7.88, 3.15 Hz,1 H), 1.45 (d, J = 6.30 Hz, 3 H). 95 MS: 356.2 (M + H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ ppm 9.71 (d, J = 8.59 Hz, 1 H) 8.76 (d, J = 8.02 Hz, 1H) 8.09 (s, 1 H) 7.25 (dd, J = 9.45, 3.15 Hz, 1 H) 7.02- 7.09 (m, 1 H)6.95-7.00 (m, 1 H) 6.71 (d, J = 8.02 Hz, 1 H) 5.68 (dd, J = 14.89, 1.15Hz, 1 H) 4.34 (dd, J = 9.45, 1.43 Hz, 1 H) 4.24-4.30 (m, 1 H) 4.10 (d, J= 14.89 Hz, 1 H) 3.94 (dd, J = 9.74, 4.01 Hz, 1 H) 3.58 (s, 3 H) 1.36(d, J = 6.87 Hz, 3 H). 96 MS: 372.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 8.64 (d, J = 8.23 Hz, 1 H) 8.27 (br s, 1 H) 8.08 (s, 1 H) 7.15 (brd, J = 6.59 Hz, 1 H) 7.04-7.10 (m, 1 H) 6.96-7.02 (m, 1 H) 6.66 (d, J =8.23 Hz, 1 H) 5.11 (br s, 1 H) 4.28 (br s, 2 H) 4.15 (br s, 1 H) 4.06(br s, 1 H) 3.90 (br s, 2 H) 3.57 (s, 3 H) 3.29 (br s, 1 H). 97 MS:356.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.49 (dd, J = 7.45, 2.86Hz, 1 H), 8.77 (d, J = 8.02 Hz, 1 H), 8.09 (s, 1 H), 7.15 (dd, J = 9.74,2.86 Hz, 1 H), 7.04-7.10 (m, 1 H), 6.97-7.03 (m, 1 H), 6.73 (d, J = 8.02Hz, 1 H), 5.54 (dd, J = 14.89, 1.72 Hz, 1 H), 4.50-4.60 (m, 1 H), 4.08(d, J = 15.47 Hz, 1 H), 3.84- 3.92 (m, 1 H), 3.59 (s, 3 H), 3.16 (ddd, J= 13.46, 7.73, 2.86 Hz, 1 H), 1.45 (d, J = 6.30 Hz, 3 H). 98 MS: 358.2(M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.76 (dd, J = 7.45, 2.29 Hz, 1H), 8.82 (d, J = 6.87 Hz, 1 H), 8.58 (d, J = 7.45 Hz, 1 H), 8.05 (s, 1H), 7.06-7.15 (m, 1 H), 6.99-7.04 (m, 2 H), 6.45 (d, J = 8.02 Hz, 1 H),5.57-5.66 (m, 1 H), 5.16-5.25 (m, 1 H), 4.52 (dt, J = 10.17, 3.79 Hz, 1H), 3.99 (td, J = 9.74, 4.01 Hz, 1 H), 3.87 (ddt, J = 13.82, 7.52, 3.94,3.94 Hz, 1 H), 3.71 (ddd, J = 11.17, 8.31, 6.30 Hz, 1 H), 3.59 (dt, J =11.17, 5.01 Hz, 1 H), 3.36-3.45 (m, 1 H). 99 MS: 372.2 (M + H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.72 (d, J = 8.02 Hz, 1 H), 8.53 (d, J = 7.45Hz, 1 H), 8.40 (t, J = 4.01 Hz, 1 H), 8.04 (s, 1 H), 7.09 (dd, J = 9.16,2.86 Hz, 1 H), 6.95-7.05 (m, 2 H), 6.42 (d, J = 7.45 Hz, 1 H), 5.63-5.72(m, 1 H), 5.16 (t, J = 5.44 Hz, 1 H), 4.29-4.37 (m, 1 H), 4.19-4.27 (m,1 H), 3.65 (ddd, J = 11.17, 8.31, 6.30 Hz, 1 H), 3.53-3.61 (m, 2 H),3.41-3.48 (m, 1 H), 2.00-2.18 (m, 2 H). 100 MS: 356.2 (M + H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 9.46 (dd, J = 7.16, 2.58 Hz, 1 H), 8.77 (d, J =8.02 Hz, 1 H), 8.11 (s, 1 H), 7.22 (dd, J = 9.74, 2.29 Hz, 1 H),7.01-7.06 (m, 2 H), 6.74 (d, J = 8.02 Hz, 1 H), 6.20-6.30 (m, 1 H), 4.50(dt, J = 10.31, 4.01 Hz, 1 H), 4.05 (ddd, J = 10.31, 9.16, 4.01 Hz, 1H), 3.85 (ddt, J = 13.68, 7.52, 3.72, 3.72 Hz, 1 H), 3.38-3.49 (m, 4 H),1.53 (d, J = 7.45 Hz, 3 H). 101 MS: 400.2 (M + H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.58 (dd, J = 7.45, 2.86 Hz, 1 H), 8.50 (s, 1 H), 8.01(s, 1 H), 7.36 (dd, J = 9.16, 2.86 Hz, 1 H), 7.00- 7.14 (m, 2 H), 5.61(dd, J = 14.61, 1.43 Hz, 1 H), 4.44-4.52 (m, 1 H), 4.14 (d, J = 12.60Hz, 1 H), 4.00-4.09 (m, 2 H), 3.81-3.92 (m, 2 H), 3.39-3.47 (m, 1 H),1.40 (s, 3 H), 1.38 (s, 3 H). 102 MS: 327.2 (M + H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.58-9.70 (m, 1 H), 9.09 (d, J = 6.87 Hz, 1 H), 8.42 (s,1 H), 7.22 (dd, J = 9.74, 2.86 Hz, 1 H), 7.11 (d, J = 7.45 Hz, 1 H),6.84-6.97 (m, 2 H), 4.37-4.50 (m, 1 H), 3.90-4.06 (m, 3 H), 3.42-3.64(m, 3 H), 2.54-2.62 (m, 1 H). 103 MS: 341.2 (M + H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.04 (d, J = 6.87 Hz, 1 H), 8.56 (t, J = 4.01 Hz, 1 H),8.40 (s, 1 H), 7.19 (dd, J = 9.74, 2.86 Hz, 1 H), 7.06 (d, J = 6.87 Hz,1 H), 6.81-6.96 (m, 2 H), 4.19-4.29 (m, 2 H), 3.53-3.63 (m, 4 H),3.24-3.31 (m, 2 H), 2.09-2.21 (m, 2 H). 104 MS: 358.2 (M + H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.79 (d, J = 8.02 Hz, 1 H), 8.70 (dd, J = 7.45,2.86 Hz, 1 H), 8.07 (s, 1 H), 7.59 (dd, J = 8.59, 5.73 Hz, 1 H), 7.10(td, J = 8.59, 2.86 Hz, 1 H), 7.04 (dd, J = 10.02, 2.58 Hz, 1 H), 6.78(d, J = 8.02 Hz, 1 H), 5.79 (dd, J = 15.75, 1.43 Hz, 1 H), 4.17 (d, J =16.04 Hz, 1 H), 3.73-3.82 (m, 1 H), 3.59 (s, 3 H), 3.52-3.58 (m, 1 H),3.26-3.30 (m, 1 H), 3.18- 3.23 (m, 1 H). 105 MS: 411.2 (M + H)⁺. 106 MS:374.2 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.84 (d, J = 8.02 Hz, 1H), 8.09-8.19 (m, 2 H), 8.07 (s, 1 H), 7.35 (td, J = 8.45, 2.58 Hz, 1H), 7.22 (dd, J = 10.31, 2.29 Hz, 1 H), 6.86 (d, J = 8.02 Hz, 1 H), 5.75(d, J = 16.61 Hz, 1 H), 4.57 (d, J = 16.61 Hz, 1 H), 4.11-4.15 (m, 1 H),3.79-3.87 (m, 2 H), 3.59 (s, 3 H), 3.48-3.57 (m, 1 H). 107 MS: 390.2(M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.83 (d, J = 8.02 Hz, 1 H),8.12 (dd, J = 9.16, 5.73 Hz, 1 H), 8.07 (s, 1 H), 7.82 (br t, J = 5.16Hz, 1 H), 7.39 (td, J = 8.59, 2.86 Hz, 1 H), 7.14-7.21 (m, 1 H), 6.84(d, J = 7.45 Hz, 1 H), 5.37-5.54 (m, 1 H), 4.61-4.76 (m, 1 H), 3.83-3.93(m, 1 H), 3.57-3.63 (m, 5H), 3.46-3.54 (m, 1 H). 108 MS: 371.2 (M + H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.73 (br d, J = 6.87 Hz, 1 H) 9.09 (d, J= 8.00 Hz, 1 H) 8.41 (s, 1 H) 7.20 (dd, J = 9.74, 2.86 Hz, 1 H) 7.11 (d,J = 6.87 Hz, 1 H) 6.94 (dd, J = 9.16, 4.58 Hz, 1 H) 6.78-6.88 (m, 1 H)4.44 (ddd, J = 8.88, 5.44, 4.01 Hz, 1 H) 3.99-4.06 (m, 1 H) 3.88-3.97(m, 1H) 3.67-3.73 (m, 1 H) 3.47-3.53 (m, 1 H) 3.12-3.21 (m, 1 H)2.54-2.62 (m, 1 H) 1.43 (d, J = 6.30 Hz, 3 H). 109 MS: 371.2 (M + H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.43 (d, J = 2.29 Hz, 1 H) 8.73 (d, J =6.87 Hz, 1 H) 8.57 (d, J = 7.50 Hz, 1 H) 8.01 (s, 1 H) 7.16 (dd, J =9.17, 2.86 Hz, 1 H) 7.00-7.11 (m, 2 H) 6.34 (d, J = 7.45 Hz, 1 H)5.61-5.73 (m, 1 H) 4.37 (dd, J = 10.31, 4.01 Hz, 1 H) 4.00 (ddt, J =8.45, 4.30, 2.22, 2.22 Hz, 1 H) 3.88-3.96 (m, 1 H) 1.48 (d, J = 6.87 Hz,3 H) 1.42 (d, J = 7.45 Hz, 3 H). 110 MS: 371.2 (M + H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ ppm 9.95 (d, J = 8.59 Hz, 1 H) 8.79 (d, J = 6.87 Hz, 1H) 8.58 (d, J = 7.45 Hz, 1 H) 8.04 (s, 1 H) 7.16 (dd, J = 9.45, 3.15 Hz,1 H) 6.98-7.05 (m, 1 H) 6.92-6.97 (m, 1 H) 6.34 (d, J = 8.02 Hz, 1 H)5.67 (quind, J = 7.02, 7.02, 7.02, 7.02, 1.72 Hz, 1 H) 4.35 (dd, J =9.45, 1.43 Hz, 1 H) 4.20-4.30 (m, 1 H) 3.93 (dd, J = 9.74, 4.01 Hz, 1 H)1.47 (d, J = 7.45 Hz, 3 H) 1.37 (d, J = 6.87 Hz, 3 H) 111 MS: 371.2 (M +H)⁺. 112 MS: 345.2 (M + H)⁺.

Additional examples are prepared using methods analogous to thosedescribed above.

Biological Example 1 Biochemical Kinase Assays

MET/ALK/AXL/TRKs enzyme inhibition may be measured by Omnia (InvitrogenInc.) continuous fluorometric assay. Reactions are conducted in 50 μLvolumes in 96-well plates at 30° C. Mixtures contain 1 nM humanrecombinant target kinase domain, 2 μM phosphoacceptor peptide, testcompound (11-dose, 3-fold serial dilutions, 2% DMSO final) or DMSO only,0.2 mM DTT, and 10 mM MgCl₂ in 20 mM Hepes, pH 7.5, and the reactionsare initiated by addition of ATP (100 μM final concentration) followinga 20 min pre-incubation. The initial rates of phosphopeptide formationare measured over 20 min using a Tecan Safire microplate reader withwavelength settings of 360 nm for excitation and 485 nm for emission.The K, values are calculated by fitting the data to the equation forcompetitive inhibition using nonlinear regression method (GraphPadPrism, GraphPad Software, San Diego, Calif.).

Biological Example 2 Cellular Kinase Phosphorylation ELISA Assays

The experiments are performed based on the procedures described in thepublication (Christensen, J. et al., “Cytoreductive antitumor activityof PF-2341066, a novel inhibitor of anaplastic lymphoma kinase andc-Met, in experimental models of anaplastic large-cell lymphoma”, Mol.Cancer Ther. 2007, 6 (12): 3314-3322.) All experiments are done understandard conditions (37° C. and 5% CO₂). IC₅₀ values are calculated byconcentration/response curve fitting using a Microsoft Excel basedfour-parameter method. Cells are seeded in 96-well plates in mediumsupplemented with 10% fetal bovine serum (FBS) and transferred toserum-free medium [with 0.04% bovine serum albumin (BSA)] after 24 h. Inexperiments investigating ligand-dependent RTK phosphorylation,corresponding growth factors are added for up to 20 min. Afterincubation of cells with an inhibitor for 1 h and/or appropriate ligandsfor the designated times, cells are washed once with HBSS supplementedwith 1 mmol/L Na₃VO₄, and protein lysates are generated from cells.Subsequently, phosphorylation of selected protein kinases is assessed bya sandwich ELISA method using specific capture antibodies to coat96-well plates and a detection antibody specific for phosphorylatedtyrosine residues. Antibody-coated plates are (a) incubated in thepresence of protein lysates at 4° C. overnight, (b) washed seven timesin 1% Tween 20 in PBS, (c) incubated in a horseradish peroxidaseconjugated anti-total-phosphotyrosine (PY-20) antibody (1:500) for 30min, (d) washed seven times again, (e) incubated in3,3,5,5-tetramethylbenzidine peroxidase substrate (Bio-Rad) to initiatea colorimetric reaction that is stopped by adding 0.09 N H₂SO₄, and (f)measured for absorbance in 450 nm using a spectrophotometer. Cell linesthat are used for individual kinases include A549 for MET, Karpas 299for ALK, 293-AXL for AXL, PAET RKA for TRKA, and PAE-TRKB for TRKB.

Biological Example 3 Kinase Binding Assays

Kinase binding assays were performed at DiscoveRx using the generalKINOMEscan K_(d) Protocol (Fabian, M. A. et al., “A smallmolecule-kinase interaction map for clinical kinase inhibitors,” Nat.Biotechnol. 2005, 23(3):329-36). For most assays, kinase-tagged T7 phagestrains were prepared in an E. coli host derived from the BL21 strain.E. coli were grown to log-phase and infected with T7 phage and incubatedwith shaking at 32° C. until lysis. The lysates were centrifuged andfiltered to remove cell debris. The remaining kinases were produced inHEK-293 cells and subsequently tagged with DNA for qPCR detection.Streptavidin-coated magnetic beads were treated with biotinylated smallmolecule ligands for 30 minutes at room temperature to generate affinityresins for kinase assays. The liganded beads were blocked with excessbiotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05%Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecificbinding. Binding reactions were assembled by combining kinases, ligandedaffinity beads, and test compounds in 1×binding buffer (20% SeaBlock,0.17×PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed inpolystyrene 96-well plates in a final volume of 0.135 mL. The assayplates were incubated at room temperature with shaking for 1 hour andthe affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20).The beads were then re-suspended in elution buffer (1×PBS, 0.05% Tween20, 0.5 μM non-biotinylated affinity ligand) and incubated at roomtemperature with shaking for 30 minutes. The kinase concentration in theeluates was measured by qPCR. Results for compounds tested in this assayare presented in Table 2. With this method, Example 20 also had abinding affinity with PLK4 kinase (K_(d) 2.9 nM).

TABLE 2 TRKA TRKB TRKC JAK1 JAK2 JAK3 ALK ROS1 Ex. K_(d) (nM) K_(d) (nM)K_(d) (nM) K_(d) (nM) K_(d) (nM) K_(d) (nM) K_(d) (nM) K_(d) (nM) 11-11900 >30000 1900 20 0.031 0.18 0.30 >1000 4.8 120 80 21 39 0.23 27 1804.7 40 600 410 41 6.00 280 2.6 33 200 42 0.088 43 0.086 3.7 45 0.082 7.849 0.14 24 50 0.20 0.57 51 0.065 65 0.15 4.3 51-1 0.051 37 0.048 1.8 6.80.73 52 6.5 270 62 75 0.015 6.5 92 0.12 8.2 93 0.082 5.7 98 0.74 14 103 1.9 28

Biological Example 4 Ba/F3 Cell Proliferation Assay

TRKA Ba/F3 cell proliferation assays were performed by ACD (AdvancedCellular Dynamics). Ba/F3 cell lines were maintained in RPMI-1640culture media containing 10% fetal bovine serum and antibiotics. Cellsin logarithmic-phase growth were harvested and 5,000 cells weredistributed into each well of a 384-well plate in 50 μL of growth media.Fifty nanoliters diluted compound were added to appropriate wells, induplicate, and the cells were cultured for 48 hours at 37° C. in ahumidified 5% CO₂ incubator. Viability was determined by adding 15 μLCellTiter-Glo and measuring luminescence, which is reported as relativelight units (RLU) measured in counts per second. The data (RLU) for eachcompound were normalized to the average maximal response obtained in thepresence of vehicle (DMSO) alone. These data were used to derive thepercent inhibition (100—% maximal response) and the average of two datapoints/concentration was used to calculate the IC₅₀ values(concentration causing a half-maximal inhibition of cell survival) vianon-linear regression analysis using GraphPad Prism software (GraphPad,Inc., San Diego, Calif.). With this method, Example 20 inhibited cellproliferation of TRKA Ba/F3 cells with an IC₅₀ of 3.0 nM. Data forcompounds tested in this assay are presented in Table 3.

Biological Example 5 EML4-ALK Ba/F3 Stable Cell Line Creation and CellProliferation Assay

The EML4-ALK wild-type gene (variant 1) was synthesized at GenScript andcloned into pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences, Inc).Ba/F3-EML4-ALK wild type cell line was generated by infecting Ba/F3cells with lentivirus containing EML4-ALK wide-type. Stable cell lineswere selected by puromycin treatment, followed by IL-3 withdrawal. 5000cells were seeded in 384 well white plate overnight before compoundtreatment. Cell proliferation was measured using CellTiter-Gloluciferase-based ATP detection assay (Promega) following themanufactures's protocol after 48 hours of various concentration ofcompound incubation. IC₅₀ determinations were performed using GraphPadPrism software (GraphPad, Inc., San Diego, Calif.). Data for compoundstested in this assay are presented in Table 3

Biological Example 6 Cell Proliferation Assays

Colorectal cell lines KM 12 (harboring endogenous TPM3-TRKA fusion gene)cells were cultured in DMEM medium, supplemented with 10% fetal bovineserum and 100 U/mL of penicillin/streptomycin. 5000 cells were seeded in384 well white plate for 24 hours before compounds treatment. Cellproliferation was measured using CellTiter-Glo luciferase-based ATPdetection assay (Promega) following the manufactures's protocol after 72hours incubation. IC₅₀ determinations were performed using GraphPadPrism software (GraphPad, Inc., San Diego, Calif.).

Alternatively: Colorectal cell line KM12 (harboring endogenous TPM3-TRKAfusion gene) cells were cultured in DMEM medium, supplemented with 10%fetal bovine serum and 100 U/mL of penicillin/streptomycin. Essentialthrombocythemia cell line SET-2 cells (harboring endogenous JAK2 V618Fpoint mutation) or T cell lymphoma Karpas-299 cell line (harboringendogenous NPM-ALK fusion gene) were cultured in RPMI medium,supplemented with 10% fetal bovine serum and 100 U/mL ofpenicillin/streptomycin. 5000 cells were seeded in 384 well white platefor 24 hours before compounds treatment. Cell proliferation was measuredusing CellTiter-Glo luciferase-based ATP detection assay (Promega)following the manufactures's protocol after 72 hours incubation. IC₅₀determinations were performed using GraphPad Prism software (GraphPad,Inc., San Diego, Calif.).

Data for compounds tested in these assays are presented in Table 3.

TABLE 3 KM 12 SET2 cell Karpas 299 EML4-ALK cell prolif. proli. cellproli. Ba/F3 cell proli. Ex. IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)11-1 >10000 >10000 >10000 20 0.86 2000 1000 39 3.8 8800 3800 40204 >10000 >10000 41 118 1500 3900 42 4.0 2000 3400 43 2.6 1700 2800 449.9 2030 4100 45 0.35 8000 >10000 46 1.5 7000 7100 47 31 >10000 >1000048 62 6000 6000 49 6.7 7000 3900 50 74 6000 4100 51 3.2 425 832 51-1 1.3234 289 248 52 52 3600 7800 59 >1000 60 >1000 61 0.6 3747 3900 62 0.94000 66 17.5 1543 1900 67 2.8 1231 1200 75 0.6 4436 3900 76-1 5.8 10033800 84 0.8 3146 4200 85 0.9 928 1080 86 1998 1000 87 0.3 2734 1591 8850.4 1900 3129 89 0.2 859 1398 90 1.8 5911 1653 91 1.8 1536 961 92 0.3142 88.7 78.6 93 0.5 242 23.7 21.1 94 0.2 >10000 >10000 95 0.4 2673 410796 0.6 6000 5000 97 0.3 6500 1419 98 7.4 808 281 99 6.3 6848 506 100 0.65834 5364 101 >1000 6000 >10000 102 1.2 2450 2304 103 15 >10000 1956 1040.3 2353 5747 105 500 >10000 >5000 106 176 >10000 >10000 107 75.63000 >10000 108 3.6 870 619 109 0.86 398 225 110 0.7 219 163 111 76 1996329

Biological Example 7 Cellular Mechanism of Action Studies-TRKA andDownstream Signal Targets Phosphorylation Assays

Colorectal cell lines KM 12 (harboring endogenous TPM3-TRKA fusion gene)cells were cultured in DMEM medium, supplemented with 10% fetal bovineserum and 100 U/mL of penicillin/streptomycin. One million cells wereseeded in 6-well plate for 24 hours before compounds treatment. Cellswere washed with 1×PBS and collected after 5 hours treatment and lysedin RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5%Deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, Halt protease andphosphatase inhibitors (Thermo Scientific). Protein lysates (20 μg) wereresolved on 4-12% Bolt Bis-Tris precasted gels with MES running buffer(Life Technologies), transferred to nitrocellulose membranes usingTrans-Blot Turbo Transfer System (Bio-Rad) and detected with antibodiestargeting phosphorylated TRK A (Cell Signaling Technology, Y496, Y680,Y681, clone C50F3; 1:1000 dilution), total TRK A (Santa CruzBiotechnology, sc-11; clone C-14, 1:2000 dilution), phosphorylated AKT(Cell signaling, S473, D9E, #9271; 1:5000 dilution), total AKT (CellSignaling Technology, 40D4; 1:2000 dilution), phosphorylated ERK (CellSignaling Technology, Thr 202/204, D13.14.4E, #4370; 1:2000 dilution),total ERK (Cell Signaling Technology; 1:1000 dilution) and Tubulin(Sigma, T4026, 1:5000 dilution). Antibodies were typically incubatedovernight at 4° C. with gentle shaking, followed by washes andincubation with the appropriate HRP-conjugated secondary antibodies.Membranes were exposed to chemiluminescent substrate for 5 min at roomtemperature (SuperSignal West Femto, Thermo Scientific). Images wereobtained with a C-Digit Imaging System (LI-COR Biosciences). Therelative density of the bands was obtained directly via Image StudioDigits from LICOR. The half inhibitory concentration (IC₅₀) values werecalculated using non-linear regression analysis through GraphPad Prismsoftware (GraphPad, Inc., San Diego, Calif.). With this method, Example20 inhibited autophosphorylation of TPM3-TRKA with an IC₅₀ of 1.07 nMand the phosphorylation of its downstream signaling targets AKT and ERKwith IC₅₀'s of 2.80 nM and 2.00 nM, respectively, in KM12 cells.

Biological Example 8 Caspase Activity Assays

KM12 cells were maintained in DMEM medium supplemented with 10% fetalbovine serum and antibiotics. 500,000 cells were seeded in 12-well plateand various concentration of compounds were introduced for 72 hours Forstaurosporine treatment, 500 nM of STS were added at time of 60 hoursand incubation of 12 hours as a positive control. All the cells werecollected and washed with 1×PBS twice and then lysed in a lysis buffer(20 mM HEPES, 150 mM NaCl, 10 mM KCl, 5 mM EDTA, 1% NP40) supplementedwith Halt protease and phosphatase inhibitors (Thermo Scientific). Forcaspase assays, around 20 μL (20 μg) of cell lysate were incubated with20 μL of caspase3 glo reagent (Promega), measuring enzyme activity bythe release of luminescence after 20 min incubation at 37° C. Forwestern blotting, cell lysates were boiled and analyzed bySDS-PAGE/immunoblotting using PARP, or actin antibodies. With thismethod, Example 20 induced apoptosis of KM 12 cells.

1. A compound of the following Formula (I-A):

wherein Ring A′ and Ring B′ are each independently a monocyclic or bicyclic aryl or heteroaryl; wherein one of Ring A′ and Ring B′ is a monocyclic aryl or heteroaryl and the other is a bicyclic heteroaryl; and at least one of Ring A′ and Ring B′ comprises at least one nitrogen ring member; each L¹ and L² is independently —C(R^(1′))(R^(2′))—, —O—, —N(R^(k′))—, —S—, —S(O)— or —S(O)₂—; each R^(1′) and R^(2′) are independently H, deuterium, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl, —OR^(a′), —OC(O)R^(a′), —OC(O)NR^(a′)R^(b′), —OS(O)R^(a′), —OS(O)₂R^(a′), —SR^(a′), —S(O)R^(a′), —S(O)₂R^(a′), —S(O)NR^(a′)R^(b′), —S(O)₂NR^(a′)R^(b′), —OS(O)NR^(a′)R^(b′), —OS(O)₂NR^(a′)R^(b′), —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)OR^(b′), —NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)S(O)R^(b′), —NR^(a′)S(O)₂R^(b′), —NR^(a′)S(O)NR^(a′)R^(b′), —NR^(a′)S(O)₂NR^(a′)R^(b′), —C(O)R^(a′), —C(O)OR^(a′), —C(O)NR^(a′)R^(b′), —PR^(a′)R^(b′), —P(O)R^(a′)R^(b′), —P(O)₂R^(a′)R^(b′), —P(O)NR^(a′)R^(b′), —P(O)₂NR^(a′)R^(b′), —P(O)OR^(a′), —P(O)₂OR^(a′), —CN, or —NO₂, or R^(1′) and R^(2′) taken together with the carbon or carbons to which they are attached form a C₃₋₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(e′), —OC(O)R^(e′), —OC(O)NR^(e′)R^(f′), —OS(O)R^(e′), —OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′), —OS(O)₂NR^(e′)R^(f′), —SR^(e′), —S(O)R^(e′), —S(O)₂R^(e′), —S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′)R^(f′), —NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′), —NR^(e′)C(O)NR^(e′)R^(f′), —NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′), —NR^(e′)S(O)NR^(e′)R^(f′), —NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′), —C(O)OR^(e′), —C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′), —P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′), —P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂; each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(e′), —OC(O)R^(e′), —OC(O)NR^(e′)R^(f′), —OS(O)R^(e′), —OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′), —OS(O)₂NR^(e′)R^(f′), —SR^(e′), —S(O)R^(e′), —S(O)₂R^(e′), —S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′)R^(f′), —NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′), —NR^(e′)C(O)NR^(e′)R^(f′), —NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′), —NR^(e′)S(O)NR^(e′)R^(f′), —NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′), —C(O)OR^(e′), —C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′), —P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′), —P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂; each R^(3′) and R^(4′) is independently deuterium, halogen, —OR^(c′), —OC(O)R^(c′), —OC(O)NR^(c′)R^(d′), —OC(═N)NR^(c′)R^(d′), —OS(O)R^(c′), —OS(O)₂R^(c′), —OS(O)NR^(c′)R^(d′), —OS(O)₂NR^(c′)R^(d′), —SR^(c′), —S(O)R^(c′), —S(O)₂R^(c′), —S(O)NR^(c′)R^(d′), —S(O)₂NR^(c′)R^(d′), —NR^(c′)R^(d′), —NR^(c′)C(O)R^(d′), —NR^(c′)C(O)OR^(d′), —NR^(c′)C(O)NR^(c′)R^(d′), —NR^(c′)C(═N)NR^(c′)R^(d′), —NR^(c′)S(O)R^(d′), —NR^(c′)S(O)₂R^(d′), —NR^(c′)S(O)NR^(c′)R^(d′), —NR^(c′)S(O)₂NR^(c′)R^(d′), —C(O)R^(c′), —C(O)OR^(c′), —C(O)NR^(c′)R^(d′), —C(═N)NR^(c′)R^(d′), —PR^(c′)R^(d′), —P(O)R^(c′)R^(d′), —P(O)₂R^(c′)R^(d′), —P(O)NR^(c′)R^(d′), —P(O)₂NR^(c′)R^(d′), —P(O)OR^(c′), —P(O)₂OR^(c′), —CN, —NO₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl, or any two R^(3′) groups or any two R^(4′) groups taken together with the ring to which they are attached form a C₅₋₈cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, mono- or bicyclic heteroaryl C₅₋₈cycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(e′), —OC(O)R^(e′), —OC(O)NR^(e′)R^(f′), —OS(O)R^(e′), —OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′), —OS(O)₂NR^(e′)R^(f′), —SR^(e′), —S(O)R^(e′), —S(O)₂R^(e′), —S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′)R^(f′), —NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′), —NR^(e′)C(O)NR^(e′)R^(f′), —NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′), —NR^(e′)S(O)NR^(e′)R^(f′), —NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′), —C(O)OR^(e′), —C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′), —P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′), —P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂; R^(7′) is H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, —OR^(i′), —OC(O)R^(i′), —OC(O)NR^(i′)R^(j′), —OS(O)R^(i′), —OS(O)₂R^(i′), —OS(O)NR^(i′)R^(j′), —OS(O)₂NR^(i′)R^(j′), —SR^(i′), —S(O)R^(i′), —S(O)₂R^(i′), —S(O)NR^(i′)R^(j′), —S(O)₂NR^(i′)R^(j′), —NR^(i′)R^(j′), —NR^(i′)C(O)R^(j′), —NR^(i′)C(O)OR^(j′), —NR^(i′)C(O)NR^(i′)R^(j′), —NR^(i′)S(O)R^(j′), —NR^(i′)S(O)₂R^(j′), —NR^(i′)S(O)NR^(i′)R^(j′), —NR^(i′)S(O)₂NR^(i′)R^(j′), —C(O)R^(i′), —C(O)OR^(i′), —C(O)NR^(i′)R^(j′), —PR^(i′)R^(j′), —P(O)R^(i′)R^(j′), —P(O)₂R^(i′)R^(j′), —P(O)NR^(i′)R^(j′), —P(O)₂NR^(i′)R^(j′), —P(O)OR^(i′), —P(O)₂OR^(i′), —CN, or —NO₂; each R^(a′), R^(b′), R^(c′), R^(d′), R^(e′), R^(f′), R^(i′) and R^(j′) is independently selected from the group consisting of H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, and heteroaryl; m′ is 2, 3, 4, or 5; n′ is 2, 3, or 4; p′ is 0, 1, 2, 3, or 4; and q′ is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1, wherein Ring A′ is monocyclic aryl or heteroaryl and Ring B′ is bicyclic heteroaryl, or a pharmaceutically acceptable salt thereof. 3-5. (canceled)
 6. The compound of claim 1, wherein Ring A′ is phenyl or pyridyl, or a pharmaceutically acceptable salt thereof. 7-11. (canceled)
 12. The compound of claim 1, wherein Ring B′ is:

or a pharmaceutically acceptable salt thereof. 13-14. (canceled)
 15. The compound of claim 1, wherein each R^(3′) is independently fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF₃, or a pharmaceutically acceptable salt thereof.
 16. The compound of claim 15, wherein each R^(3′) is fluoro or chloro, or a pharmaceutically acceptable salt thereof. 17-18. (canceled)
 19. The compound of claim 1, wherein R^(7′) is H or is methyl or ethyl, each unsubstituted or substituted with halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, cycloalkyl, or monocyclic heterocycloalkyl, or a pharmaceutically acceptable salt thereof. 20-26. (canceled)
 27. The compound of claim 1, wherein each R^(k′) is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl, or a pharmaceutically acceptable salt thereof.
 28. (canceled)
 29. The compound of claim 1, wherein -(L¹)_(n′)- is —CH₂—O—, CH(C₁₋₄alkyl)-O—, —CH(C₃₋₆cycloalkyl)-O—; or CH(H or optionally substituted C₁₋₄alkyl)-N(H or optionally substituted C₁₋₄alkyl)-, —CH(CO₂C₁₋₄alkyl or C(O)N(H or C₁₋₄alkyl)₂)-N(H or optionally substituted C₁₋₄alkyl), or a pharmaceutically acceptable salt thereof.
 30. The compound of claim 29, wherein -(L²)_(m′) is —O—(C(R^(1′))(R^(2′)))₂₋₃—, —O—(CH₂)₂₋₃—, —N(R^(k′))—(C(R^(1′))(R^(2′)))₂₋₃—, —N(H or C₁₋₄alkyl)-(CH₂)₂₋₃—, —S—(C(R^(1′))(R^(2′)))₂₋₃—, —SO₂—(C(R^(1′))(R^(2′)))₂₋₃—, —SO₂—N(R^(k′))(C(R^(1′))(R^(2′)))₂— or —(C(R^(1′))(R^(2′)))₃—, or a pharmaceutically acceptable salt thereof.
 31. The compound of claim 30, wherein m′ is 3, or a pharmaceutically acceptable salt thereof.
 32. The compound of claim 31, wherein n′ is 2, or a pharmaceutically acceptable salt thereof.
 33. The compound of claim 32, wherein p′ is 1, or a pharmaceutically acceptable salt thereof.
 34. The compound of claim 33, wherein q′ is 0, or a pharmaceutically acceptable salt thereof.
 35. A compound of the Formula (IV):

wherein M is CH or N; X¹ and X¹′ are independently —C(R^(1a))(R^(2a))—, —S—, —S(O)—, —S(O)₂—, —O— or —N(R^(k′))—; each R^(1a) and R^(2a) is independently H, deuterium, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, —C(O)OR^(a′), —C(O)NR^(a′)R^(b′), —NR^(a′)R^(b′), —SR^(a′), —S(O)R^(a′), —S(O)NR^(a′), —S(O)₂R^(a′), —S(O)₂NR^(a′) or —OR^(a′) wherein each hydrogen atom in C₁₋₆alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, NHC(O)C₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)C₁₋₄alkyl, —NHC(O)NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)NHC₁₋₄alkyl, —NHC(O)N(C₁₋₄alkyl)₂, —N(C₁₋₄alkyl)C(O)N(C₁₋₄alkyl)₂, —NHC(O)OC₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)OC₁₋₄alkyl, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —S(O)NH(C₁₋₄alkyl), —S(O)₂NH(C₁₋₄alkyl), —S(O)N(C₁₋₄alkyl)₂, —S(O)₂N(C₁₋₄alkyl)₂, C₃₋₆cycloalkyl, or 3- to 7-membered heterocycloalkyl; R^(3a) and R^(3b) are each independently H, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF₃; R^(7a) is H, C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, —CN, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, cycloalkyl, or monocyclic heterocycloalkyl; each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl in R^(k)′ is independently optionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl or —OR^(a′); wherein each R^(a′) and R^(b′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or heteroaryl; each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R^(x)), wherein each R^(x) when present is independently H, deuterium, halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF₃, provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH; and m′ is 2 or 3; or a pharmaceutically acceptable salt thereof.
 36. A compound of the Formula (V):

wherein M is CH or N; X¹ and X¹′ are independently —C(R^(1a))(R^(2a))—, —S—, —S(O)—, —S(O)₂—, —O— or —N(R^(k′))—; each R^(1a) and R^(2a) is independently H, deuterium, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, —C(O)OR^(a′), —C(O)NR^(a′)R^(b′), —NR^(a′)R^(b′), —SR^(a′), —S(O)R^(a′), —S(O)NR^(a′), —S(O)₂R^(a′), —S(O)₂NR^(a′) or —OR^(a′) wherein each hydrogen atom in C₁₋₆alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, NHC(O)C₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)C₁₋₄alkyl, —NHC(O)NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)NHC₁₋₄alkyl, —NHC(O)N(C₁₋₄alkyl)₂, —N(C₁₋₄alkyl)C(O)N(C₁₋₄alkyl)₂, —NHC(O)OC₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)OC₁₋₄alkyl, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —S(O)NH(C₁₋₄alkyl), —S(O)₂NH(C₁₋₄alkyl), —S(O)N(C₁₋₄alkyl)₂, —S(O)₂N(C₁₋₄alkyl)₂, C₃₋₆cycloalkyl, or 3- to 7-membered heterocycloalkyl; R^(3a) and R^(3b) are each independently H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF₃; R^(7a) is H, C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, cycloalkyl, or monocyclic heterocycloalkyl; each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl in R^(k)′ is independently optionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl or —OR^(a′); wherein each R^(a′) and R^(b′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or heteroaryl; each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R^(x)), wherein each R^(x) when present is independently H, deuterium, halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF₃, provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH; and m′ is 2 or 3; or a pharmaceutically acceptable salt thereof.
 37. A compound selected from the group consisting of

wherein M is CH or N; X¹ and X¹′ are independently —C(R^(1a))(R^(2a))—, —S—, —S(O)—, —S(O)₂—, —O— or —N(R^(k′))—; each R^(1a) and R^(2a) is independently H, deuterium, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, —C(O)OR^(a′), —C(O)NR^(a′)R^(b′), —NR^(a′)R^(b′), —SR^(a′), —S(O)R^(a′), —S(O)NR^(a′), —S(O)₂R^(a′), —S(O)₂NR^(a′) or —OR^(a′) wherein each hydrogen atom in C₁₋₆alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, NHC(O)C₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)C₁₋₄alkyl, —NHC(O)NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)NHC₁₋₄alkyl, —NHC(O)N(C₁₋₄alkyl)₂, —N(C₁₋₄alkyl)C(O)N(C₁₋₄alkyl)₂, —NHC(O)OC₁₋₄alkyl, —N(C₁₋₄alkyl)C(O)OC₁₋₄alkyl, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —S(O)NH(C₁₋₄alkyl), —S(O)₂NH(C₁₋₄alkyl), —S(O)N(C₁₋₄alkyl)₂, —S(O)₂N(C₁₋₄alkyl)₂, C₃₋₆cycloalkyl, or 3- to 7-membered heterocycloalkyl; R^(3a) and R^(3b) are each independently H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF₃; R^(7a) is H, C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C₁₋₆alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CO₂H, —CO₂C₁₋₄alkyl, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, cycloalkyl, or monocyclic heterocycloalkyl; each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl in R^(k)′ is independently optionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl or —OR^(a′); wherein each R^(a′) and R^(b′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or heteroaryl; each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R^(x)), wherein each R^(x) when present is independently H, deuterium, halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF₃, provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH; and m′ is 2 or 3; or a pharmaceutically acceptable salt thereof. 38-40. (canceled)
 41. The compound of claim 37, wherein M is CH, Z¹, Z⁴ and Z⁷ are N, Z², Z³, Z⁵ and Z⁶ are C(R^(x)), wherein each R^(x) when present is H, X¹ is —N(R^(k′))—, and X^(1′) is —O—, or a pharmaceutically acceptable salt thereof. 42.-44. (canceled)
 45. The compound of claim 1 selected from the group consisting of (13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 2-[(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide; 2-[12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide; (13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-7-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; (7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one; (5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one; 3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one; (5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one; 3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one; (13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one; (7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)pyrrolo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)imidazo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-etheno[1,2,4]triazolo[3,4-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)[1,2,4]triazolo[3,4-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-16(13H)-one; 12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(azenometheno)pyrrolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one; (8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; 10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; (7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one; and 9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one; or a pharmaceutically acceptable salt thereof.
 46. The compound of claim 1 selected from the group consisting of 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-3,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; 10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one; 14-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 14-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide; 11-fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide; 11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide; 11-fluoro-7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; methyl 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxylate; 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one; 13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-4(5H)-one; 13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 14,14-dioxide; 6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][10,1,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; 14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one; 13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one; 11-fluoro-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide; 11-fluoro-14-methyl-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide; 12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; 12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; (14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e][2,4,10]benzotriazacyclotridecin-8-one; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzoxatriazacyclotridecin-8(5H)-one; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e][2,4,7,10]benzotetraazacyclotridecin-8-one; 11-fluoro-4,7,14-trimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e][2,4,7,10]benzotetraazacyclotridecin-8-one; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzothiatriazacyclotridecin-8(5H)-one; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzothiatriazacyclotridecin-8(5H)-one 4,4-dioxide; and 12-fluoro-8,15-dimethyl-5,6,7,8,14,15-hexahydro-9H-1,16-ethenopyrazolo[3,4-e][7,2,4,8,11]benzothiatetraazacyclotetradecin-9-one 4,4-dioxide; or a pharmaceutically acceptable salt thereof.
 47. The compound of claim 1 selected from the group consisting of 11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-methyl(6,6,7,7-²H₄)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-(cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (7R,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; (7S,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; (7R,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-fluoro-7-hydroxy-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; (7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; 11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 12-fluoro-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9]benzoxadiazacyclotetradecin-4-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4 (5H)-one; 11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 8-oxide; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 8,8-dioxide; (7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8]benzoxadiazacyclotridecin-4(5H)-one; (6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (6R,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; and 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; or a pharmaceutically acceptable salt thereof.
 48. The compound of claim 1 having the formula

or a pharmaceutically acceptable salt thereof.
 49. A crystalline form of the free base of the compound of the formula

having a powder X-ray diffraction pattern substantially the same as FIG.
 1. 50.-54. (canceled)
 55. A pharmaceutical composition comprising (a) at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.
 56. A method of treating cancer, pain, a neurological disease, an autoimmune disease, and inflammation, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof. 